The Martha Meier Weiland Professor in the School of Medicine and Professor of Bioengineering and, by courtesy, of Mechanical Engineering

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Bio

Yock began his faculty career as an interventional cardiologist at UC San Francisco and then moved to Stanford in 1994. Yock is known for his work in inventing, developing and testing new devices, including the Rapid Exchange angioplasty and stenting system, which is the primary approach used worldwide. Yock also authored the fundamental patents for intravascular ultrasound imaging, conducted the initial clinical trials and established the Stanford Center for Research in Cardiovascular Interventions as a core laboratory for analysis of intravascular ultrasound clinical studies. He also invented the Smart Needle and is a co-inventor of the strain-reduction patch for wound healing. Yock was founding Co-Chair of the Department of Bioengineering and continues research related to new device technologies. Yock also founded and is the Director of the Program in Biodesign, a unit of Bio-X dedicated to advanced training in medical technology innovation.

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Research & Scholarship

Current Research and Scholarly Interests

Founder and Director of the Byers Center for Biodesign, a multidisciplinary training and support program for physicians and engineers with the ambition and talent to become health technology innovators. The Center has educational/training programs at multiple levels including a postgraduate fellowship, multiple graduate and undergraduate classes and a faculty training program. In addition, Biodesign administers seed grant programs and a mentoring system for faculty and students who seek to translate health technology innovations into patient care.

Abstract

Although cardiac allograft vasculopathy (CAV) is typically characterized by diffuse coronary intimal thickening with pathological vessel remodeling, plaque instability may also play an important role in CAV. Previous studies of native coronary atherosclerosis have demonstrated associations between attenuated-signal plaque (ASP), plaque instability, and adverse clinical events.This study's aim was to characterize the association between ASP and long-term mortality post-heart transplantation.In 105 heart transplant recipients, serial (baseline and 1-year post-transplant) intravascular ultrasound was performed in the first 50 mm of the left anterior descending artery. The ASP score was calculated by grading the measured angle of attenuation from grades 0 to 4 (specifically, 0°, 1° to 90°, 91° to 180°, 181° to 270°, and >270°) at 1-mm intervals. The primary endpoint was all-cause death or retransplantation.At 1-year post-transplant, 10.5% of patients demonstrated ASP progression (newly developed or increased ASP). Patients with ASP progression had a higher incidence of acute cellular rejection during the first year (63.6% vs. 22.3%; p = 0.006) and tendency for greater intimal growth (percent intimal volume: 9.2 ± 9.3% vs. 4.4 ± 5.3%; p = 0.07) than those without. Over a median follow-up of 4.6 years, there was a significantly lower event-free survival rate in patients with ASP progression at 1-year post-transplant compared with those without. In contrast, maximum intimal thickness did not predict long-term mortality.ASP progression appears to reflect chronic inflammation related to acute cellular rejection and is an independent predictor of long-term mortality after heart transplantation. Serial assessments of plaque instability may enhance identification of high-risk patients who may benefit from closer follow-up and targeted medical therapies.

Abstract

Our aim was to evaluate stent expansion and acute recoil at deployment and post-dilatation, and the impact of post-dilatation strategies on final stent dimensions.Optical coherence tomography (OCT) was performed on eight bare metal platforms of drug-eluting stents (3.0 mm diameter, n=6 for each) during and after balloon inflation in a silicone mock vessel. After nominal-pressure deployment, a single long (30 sec) vs. multiple short (10 sec x3) post-dilatations were performed using a non-compliant balloon (3.25 mm, 20 atm). Stent areas during deployment with original delivery systems were smaller in stainless steel stents than in cobalt-chromium and platinum-chromium stents (p<0.001), whereas subsequent acute recoil was comparable among the three materials. At post-dilatation, acute recoil was greater in cobalt-chromium and platinum-chromium stents than in stainless steel stents (p<0.001), resulting in smaller final stent areas in cobalt-chromium and platinum-chromium stents than in stainless steel stents (p<0.001). In comparison between conventional and latest-generation cobalt-chromium stents, stent areas were not significantly different after both deployment and post-dilatation. With multiple short post-dilatations, acute recoil was significantly improved from first to third short inflation (p<0.001), achieving larger final area than a single long inflation, despite stent materials/designs (p<0.001).Real-time OCT revealed significant acute recoil in all stent types. Both stent materials/designs and post-dilatation strategies showed a significant impact on final stent expansion.

Abstract

This study investigated the relationship between periarterial neovascularization, development of cardiac allograft vasculopathy (CAV), and long-term clinical outcomes after heart transplantation. Proliferation of the vasa vasorum is associated with arterial inflammation. The contribution of angiogenesis to the development of CAV has been suggested.Serial (baseline and 1-year post-transplant) intravascular ultrasound was performed in 102 heart transplant recipients. Periarterial small vessels (PSV) were defined as echolucent luminal structures <1 mm in diameter, located ≤2 mm outside of the external elastic membrane. The signal void structures were excluded when they connected to the coronary lumen (considered as side branches) or could not be followed in ≥3 contiguous frames. The number of PSV was counted at 1-mm intervals throughout the first 50 mm of the left anterior descending artery, and the PSV score was calculated as the sum of cross-sectional values. Patients with a PSV score increase of ≥ 4 between baseline and 1-year post-transplant were classified as the "proliferative" group. Maximum intimal thickness was measured for the entire analysis segment.During the first year post-transplant, the proliferative group showed a greater increase in maximum intimal thickness (0.33 ± 0.36 mm vs 0.10 ± 0.28 mm, p < 0.001) and had a higher incidence of acute cellular rejection (50.0% vs 23.9%, p = 0.025) than the non-proliferative group. On Kaplan-Meier analysis, cardiac death-free survival rate over a median of 4.7 years was significantly lower in the proliferative group than in the non-proliferative group (hazard ratio, 3.10; p = 0.036).The increase in PSV, potentially representing an angioproliferative response around the coronary arteries, was associated with early CAV progression and reduced survival after heart transplantation.

Abstract

The presence of a myocardial bridge (MB) has been shown to promote atherosclerotic plaque formation proximal to the MB, presumably because of hemodynamic disturbances provoked by retrograde blood flow toward this segment in cardiac systole. We aimed to determine the anatomic and functional properties of an MB related to the extent of atherosclerosis assessed by intravascular ultrasound.We enrolled 100 patients with angina but no significant obstructive coronary artery disease who had an intravascular ultrasound-detected MB in the left anterior descending artery (median age 54 years, 36% male). The MB was identified with intravascular ultrasound by the presence of an echolucent band (halo). Anatomically, the MB length was 22±13 mm, and halo thickness was 0.7±0.6 mm. Functionally, systolic arterial compression was 23±12%. The maximum plaque burden up to 20 mm proximal to the MB entrance was significantly greater than the maximum plaque burden within the MB segment. Among the intravascular ultrasound-defined MB properties, arterial compression was the sole MB parameter that demonstrated a significant positive correlation with maximum plaque burden up to 20 mm proximal to the MB entrance (r=0.254, P=0.011 overall; r=0.545, P<0.001 low coronary risk). In multivariate analysis, adjusting for clinical characteristics and coronary risk factors, arterial compression was independently associated with maximum plaque burden up to 20 mm proximal to the MB entrance.In patients with an MB in the left anterior descending artery, the percentage of arterial compression is related directly to the burden of atherosclerotic plaque located proximally to the MB, particularly in patients who otherwise have low coronary risk. This may prove helpful in identifying high-risk MB patients.

Abstract

This study investigated the association between arterial remodeling and geographic distribution of cardiac allograft vasculopathy (CAV), and outcomes after heart transplantation.CAV is characterized by a combination of coronary intimal thickening and pathological vessel remodeling, which varies at different locations in coronary arteries.In 100 transplant recipients, serial volumetric intravascular ultrasonography (IVUS) was performed at baseline and 1 year post-transplantation in the first 50 mm of the left anterior descending artery (LAD). IVUS indices were evaluated in the entire segment and 3 equally divided LAD segments. Paradoxical vessel remodeling was defined as [Δvessel volume/Δintimal volume <0].After 1 year, death or re-transplantation occurred in 20 patients over a median follow-up period of 4.7 years. Paradoxical vessel remodeling was observed in 57%, 41%, 50%, and 40% for the entire vessel, proximal, middle, and distal LAD segments, respectively. Kaplan-Meier analysis revealed a significantly lower event-free rate of survival in patients with paradoxical vessel remodeling involving the proximal LAD segment, which was not present when involving the entire LAD or mid and distal LAD segments. In multivariate analysis, paradoxical vessel remodeling of the proximal LAD segment was independently associated with death or re-transplantation (hazard ratio [HR]: 11.18; 95% confidence interval [CI]: 2.39 to 83.23; p = 0.0015).Despite the diffuse nature of CAV, paradoxical vessel remodeling of the proximal LAD segment at 1 year was the primary determinant of long-term mortality or re-transplantation. Assessment of arterial remodeling combined with coronary intimal thickening may enhance identification of high-risk patients who may benefit from closer follow-up and targeted medical therapies.

Abstract

Aims: The aim of this IVUS substudy was to assess the efficacy of the Y-shaped Medtronic bifurcation-dedicated stent (BDS) for the treatment of de novo coronary bifurcated lesions. Methods and results: In the BRANCH trial, post-procedure IVUS was performed in 45 patients. IVUS was available in both branches in 19 lesions and only the main branch (MB) in 26 lesions. IVUS analysis included four distinct locations: proximal MB, bifurcation site, distal MB, and side branch (SB). Lumen symmetry was calculated as minimum/maximum lumen diameters. The quantity of isolated stent struts across the SB ostium was used to assess inadequate strut apposition to the carina resulting in partial jailing of the SB orifice. A minimum stent area (MSA) <4 mm2 was found in 0% of proximal and distal MB, and in 15.4% of SB. In SB, MSA was located mainly at mid or distal segments (84.6%), rather than at the SB ostium. Eccentric stent expansion and edge dissection were seen primarily at proximal MB. Isolated struts were seen in only 20.9% of SB ostia with a minimum length of 0.7±0.4 mm. Conclusions: Implantation of BDS resulted in adequate stent dimensions and strut apposition at the carina and SB ostium. ClinicalTrials.gov Identifier: NCT0060732.

Abstract

To examine the comparative fate of adipose-derived stem cells (ASCs) as well as their impact on coronary microcirculation following either retrograde coronary venous (RCV) or arterial delivery.Local delivery of ASCs to the heart has been proposed as a practical approach to limiting the extent of myocardial infarction. Mouse models of mesenchymal stem cell effects on the heart have also demonstrated significant benefits from systemic (intravenous) delivery, prompting a question about the advantage of local delivery. There has been no study addressing the extent of myocardial vs. systemic disposition of ASCs in large animal models following local delivery to the myocardium.In an initial experiment, dose-dependent effects of ASC delivery on coronary circulation in normal swine were evaluated to establish a tolerable ASC dosing range for intracoronary (IC) delivery. In a set of subsequent experiments, an anterior acute myocardial infarction (AMI) was created by balloon occlusion of the proximal left anterior descending (LAD) artery, followed by either IC or RCV infusion of 10(7) (111)Indium-labeled autologous ASCs 6 days following AMI. Indices of microcirculatory resistance (IMR) and coronary flow reserve (CFR) were measured before sacrifices to collect tissues for analysis at 1 or 24 hr after cell delivery.IC delivery of porcine ASCs to normal myocardium was well tolerated up to a cumulative dose of 14 × 10(6) cells (approximately 0.5 × 10(6) cells/kg). There was evidence suggesting microcirculatory trapping of ASC: at unit doses of 50 × 10(6) ASCs, IMR and CFR were found to be persistently altered in the target LAD distribution at 7 days following delivery, whereas at 10 × 10(6) ASCs, only CFR was altered. In the context of recent MI, a significantly higher percentage of ASCs was retained at 1 hr with IC delivery compared with RCV delivery (57.2 ± 12.7% vs. 17.9 ± 1.6%, P = 0.037) but this initial difference was not apparent at 24 hr (22.6 ± 5.5% vs. 18.7 ± 8.6%; P = 0.722). In both approaches, most ASC redistributed to the pulmonary circulation by 24 hr postdelivery. There were no significant differences in CFR or IMR following ASC delivery to infarcted tissue by either route.Selective intravascular delivery of ASC by coronary arterial and venous routes leads to similarly limited myocardial cell retention with predominant redistribution of cells to the lungs. IC arterial delivery of ASC leads to only transiently greater myocardial retention, which is accompanied by obstruction of normal regions of coronary microcirculation at higher doses. The predominant intrapulmonary localization of cells following local delivery via both methods prompts the notion that systemic delivery of ASC might provide similarly beneficial outcomes while avoiding risks of inadvertent microcirculatory compromise.

Abstract

The Stanford Biodesign Program began in 2001 with a mission of helping to train leaders in biomedical technology innovation. A key feature of the program is a full-time postgraduate fellowship where multidisciplinary teams undergo a process of sourcing clinical needs, inventing solutions and planning for implementation of a business strategy. The program places a priority on needs identification, a formal process of selecting, researching and characterizing needs before beginning the process of inventing. Fellows and students from the program have gone on to careers that emphasize technology innovation across industry and academia. Biodesign trainees have started 26 companies within the program that have raised over $200 million and led to the creation of over 500 new jobs. More importantly, although most of these technologies are still at a very early stage, several projects have received regulatory approval and so far more than 150,000 patients have been treated by technologies invented by our trainees. This paper reviews the initial outcomes of the program and discusses lessons learned and future directions in terms of training priorities.

Abstract

Head and neck (H&N) radiation therapy (RT) can induce irreversible damage to the salivary glands thereby causing long-term xerostomia or dry mouth in 68%-85% of the patients. Not only does xerostomia significantly impair patients' quality-of-life (QOL) but it also has important medical sequelae, incurring high medical and dental costs. In this article, we review various measures to assess xerostomia and evaluate current and emerging solutions to address this condition in H&N cancer patients. These solutions typically seek to accomplish 1 of the 4 objectives: (1) to protect the salivary glands during RT, (2) to stimulate the remaining gland function, (3) to treat the symptoms of xerostomia, or (4) to regenerate the salivary glands. For each treatment, we assess its mechanisms of action, efficacy, safety, clinical utilization, and cost. We conclude that intensity-modulated radiation therapy is both the most widely used prevention approach and the most cost-effective existing solution and we highlight novel and promising techniques on the cost-effectiveness landscape.

Abstract

The aim of this study was to evaluate a new fully automated lumen border tracing system based on a novel multifrequency processing algorithm.We developed the multifrequency processing method to enhance arterial lumen detection by exploiting the differential scattering characteristics of blood and arterial tissue. The implementation of the method can be integrated into current intravascular ultrasound (IVUS) hardware.This study was performed in vivo with conventional 40-MHz IVUS catheters (Atlantis SR Pro™, Boston Scientific Corp, Natick, MA) in 43 clinical patients with coronary artery disease. A total of 522 frames were randomly selected, and lumen areas were measured after automatically tracing lumen borders with the new tracing system and a commercially available tracing system (TraceAssist™) referred to as the "conventional tracing system." The data assessed by the two automated systems were compared with the results of manual tracings by experienced IVUS analysts.New automated lumen measurements showed better agreement with manual lumen area tracings compared with those of the conventional tracing system (correlation coefficient: 0.819 vs. 0.509). When compared against manual tracings, the new algorithm also demonstrated improved systematic error (mean difference: 0.13 vs. -1.02 mm(2) ) and random variability (standard deviation of difference: 2.21 vs. 4.02 mm(2) ) compared with the conventional tracing system.This preliminary study showed that the novel fully automated tracing system based on the multifrequency processing algorithm can provide more accurate lumen border detection than current automated tracing systems and thus, offer a more reliable quantitative evaluation of lumen geometry.

Abstract

Exaggerated neointimal hyperplasia is considered as the primary mechanism for increased restenosis in patients with diabetes mellitus (DM) treated with bare-metal stent. However, the vessel response in DM and non-DM treated with different drug-eluting stents (DES) has not been systematically evaluated.We investigated 3D intravascular ultrasound (postprocedure and 6 to 9 months) in 971 patients (267 with DM and 704 without DM) treated with sirolimus- (n=104), paclitaxel- (n=303), zotarolimus- (n=391), or everolimus- (n=173) eluting stents. Volumetric data were standardized by length as volume index (VI). At postprocedure, lumen VI at the stented segment was significantly smaller in DM than in non-DM, whereas vessel VI was similar between the 2 groups. At follow-up, neointimal obstruction and maximum cross-sectional narrowing (neointimal area/stent area) were not significantly different between the 2 groups with no interaction for the DES type. Consequently, lumen VI was smaller in DM than in non-DM at follow-up. In the reference segments, residual plaque burden at postprocedure was significantly greater in DM than in non-DM, although change in lumen VI was similar between the 2 groups. The arterial responses at the reference segments also showed no interaction for the DES type.DM and non-DM lesions showed similar vessel response in both in-stent and reference segments regardless of the DES type. In the DES era, the follow-up lumen in DM patients seems to be determined primarily by the smaller lumen at postprocedure rather than exaggerated neointima within the stent or plaque proliferation at the reference segments.

Abstract

To determine the feasibility and efficacy of applying an established innovation process to an active academic interventional radiology (IR) practice.The Stanford Biodesign Medical Technology Innovation Process was used as the innovation template. Over a 4-month period, seven IR faculty and four IR fellow physicians recorded observations. These observations were converted into need statements. One particular need relating to gastrostomy tubes was diligently screened and was the subject of a single formal brainstorming session.Investigators collected 82 observations, 34 by faculty and 48 by fellows. The categories that generated the most observations were enteral feeding (n = 9, 11%), biopsy (n = 8, 10%), chest tubes (n = 6, 7%), chemoembolization and radioembolization (n = 6, 7%), and biliary interventions (n = 5, 6%). The output from the screening on the gastrostomy tube need was a specification sheet that served as a guidance document for the subsequent brainstorming session. The brainstorming session produced 10 concepts under three separate categories.This formalized innovation process generated numerous observations and ultimately 10 concepts to potentially to solve a significant clinical need, suggesting that a structured process can help guide an IR practice interested in medical innovation.

Abstract

Recently, universities in the United States and abroad have developed dedicated educational programs in life science technology innovation. Here, we discuss the two major streams of educational theory and practice that have informed these programs: design thinking and entrepreneurship education. We make the case that the process of innovation for new medical technologies (medtech) is different from that for biopharmaceuticals and outline the challenges and opportunities associated with developing a discipline of medtech innovation.

Abstract

The influence of donor-transmitted coronary atherosclerosis (DA) on plaque progression during the first year after cardiac transplantation (Tx) is unknown.Serial 3-dimensional intravascular ultrasound (IVUS) studies were performed within 8 weeks (baseline; BL) and at 1 year after Tx in 38 recipients. On the basis of maximum intimal thickness (MIT) at BL, recipients were divided into DA group (DA+; MIT≥0.5 mm, n=23) or non-DA group (DA-; MIT<0.5 mm, n=15). Plaque, lumen, and vessel volume indexes were calculated by volume/measured length (mm/mm) in the left anterior descending artery. Univariate and multivariate regression analyses were attempted to reveal clinical predictors of change in coronary dimensions.During the first year after Tx, plaque volume index increased significantly in DA+ group, but did not change in DA- Group (DA+, 3.0±1.5 to 4.1±1.5 mm/mm, P<0.0001: DA-, 1.2±0.4 to 1.3±0.5 mm/mm, P=0.53). In both groups vessel volume index decreased significantly (DA+, 16.3±3.6 to 14.6±3.3 mm/mm, P=0.003: DA-, 13.5±4.1 to 12.0±3.3 mm/mm, P=0.01), as did lumen volume index (DA+, 13.2±3.1 to 10.5±2.7 mm/mm, P<0.0001: DA-, 12.2±3.7 to 10.7±3.0 mm/mm, P=0.004). Univariate and multivariate regression analyses revealed that DA was one of the strongest predictors for plaque progression.DA was associated with significant plaque progression during the first year after Tx, and in conjunction with negative remodeling, may be an important determinant of cardiac allograft vasculopathy.

Abstract

To assess the efficacy of the sirolimus-eluting stent when implanted in smaller caliber vessels using three-dimensional intravascular ultrasound (IVUS) analysis.One hundred and twenty-three patients (69 sirolimus-coated Bx Velocity and 54 control) who underwent successful three-dimensional IVUS at follow up comprised this IVUS substudy from the SIRIUS (SIRolImUS-coated Bx Velocity stent in the treatment of patients with de novo coronary artery lesions) population. To evaluate the impact of vessel size, 2 groups were created using QCA reference vessel diameter (RVD; large vessel group: RVD>/=2.75 mm and small vessel group: RVD<2.75 mm).Sirolimus-eluting stents significantly reduced neointimal hyperplasia by the same relative magnitude within the stent in small vessels as well as in large vessels. Although sirolimus-eluting stents had favorable effects on lumen area at stent edges in larger vessels, the effect was less in smaller vessels, especially at the proximal edge. IVUS-detected adverse vessel response, such as late-acquired incomplete apposition, did not increase in smaller vessels even with relatively higher dose exposure.Sirolimus-eluting stents showed inhibition of neointimal hyperplasia in small vessels compared to bare metal stents with no increase of vascular complications.

Abstract

The goal of this study was to assess the rate and anatomical targets of repeat revascularization procedures in routine clinical practice after either bare-metal stent (BMS) or drug-eluting stent (DES) implantation. Randomized trials provide a reference standard for comparing outcomes after BMS or DES, but the rates of repeat revascularization procedures in clinical trials do not necessarily represent the rates in routine practice.Baseline and 1-year follow-up angiographic data from a cardiac catheterization laboratory data registry with 31 participating hospitals were analyzed.In 17 hospitals 14,459 eligible patients had a BMS implanted between 1998 and 2003, and in 20 hospitals 9,575 eligible patients had a DES implanted in 2005. DES patients had more multivessel disease and diabetes than BMS patients, but fewer DES patients had all diseased vessels stented. Over the subsequent year, there were significantly fewer repeat procedures in the initially stented region after DES than BMS (4.7% vs. 8.1%), but significantly more procedures in previously unstented remote segments (7.8% vs. 4.3%). Consequently, the overall rate of additional percutaneous coronary intervention admissions was not reduced by DES (12.5% vs. 12.3%; p > 0.7).In this sample of routine clinical practice DES reduced repeat intervention of the stented segment to a lesser extent than has been reported in randomized trials. For our cohort, the reduction in restenosis was offset by increased use of additional interventional procedures to treat remote segments, predominantly within the first 2 months after initial stenting.

Abstract

Preprocedual C-reactive protein (CRP) has been reported to correlate with in-stent restenosis following bare-metal stent implantation. The aim of this study was to investigate the impact of preprocedural inflammation on neointimal hyperplasia assessed by intravascular ultrasound (IVUS) following everolimus-eluting stent (EES) implantation.We identified 134 patients meeting the following criteria: 1) patients treated with EES; 2) those with stable or unstable angina; and 3) patients available for high-sensitivity (hs)-CRP before the procedure and volumetric IVUS analysis at follow up. We divided the patients into two groups on the basis of hs-CRP levels (< 3 or > or = 3 mg/L) before the procedure and compared IVUS parameters. Volume index (volume/length) was calculated for vessel (VVI), plaque (PVI), neointima (NIV), stent (SVI), and lumen (LVI). Percent neointimal volume (%NIV) was calculated as (NIV/SVI) x 100. Cross-sectional narrowing (CSN) was defined as neointimal area divided by stent area (%).There was no significant difference in VVI, PVI, or LVI at either baseline or 8-month follow up between the two groups. At 8-month follow up, there was also no significant difference in %NIV (4.93 +/- 5.66% vs. 4.98 +/- 5.25% p = 0.959) and maximum %CSN (16.81 +/- 13.62% vs. 18.14 +/- 13.91%; p = 0.608) as well as VVI, PVI, and LVI between the two groups. Furthermore, hs-CRP did not correlate with %NIV (r = 0.044; p = 0.610) and maximum %CSN (r = 0.086, p = 0.321) at follow up. There was no significant difference in incidence of late-acquired incomplete stent apposition between the two groups (1.2% vs. 0%; p = 0.512).Our results suggest that preprocedural inflammation does not affect neointimal hyperplasia following EES implantation.

Abstract

The aim of this study was to compare the vessel response between zotarolimus-eluting stents (ZES) and paclitaxel-eluting stents (PES) using intravascular ultrasound.The ENDEAVOR IV (Randomized Comparison of Zotarolimus- and Paclitaxel-Eluting Stents in Patients With Coronary Artery Disease) trial was a randomized controlled study of zotarolimus-eluting, phosphorylcholine-coated, cobalt-alloy stents for the treatment of de novo coronary lesions compared with using PES for the same treatment.Data were obtained from patients with serial (baseline and 8-months follow-up) intravascular ultrasound analysis available (n = 198). Volumetric analysis was performed for vessel, lumen, plaque, stent, and neointima. Cross-sectional narrowing (given as percentage) was defined as neointimal area divided by stent area. Neointima-free frame ratio was calculated as the number of frames without intravascular ultrasound-detectable neointima divided by the total number of frames within the stent. Subsegment analysis was performed at every matched 1-mm subsegment throughout the stent.At follow-up, the ZES group showed significantly greater percentage of neointimal obstruction (16.6 +/- 12.0% vs. 9.9 +/- 8.9%, p < 0.01) and maximum cross-sectional narrowing (31.8 +/- 16.1% vs. 25.2 +/- 14.9%, p < 0.01) with smaller minimum lumen area than the PES group did. However, the incidence of maximum cross-sectional narrowing >50% was similar in the 2 groups. Neointima-free frame ratio was significantly lower in the ZES group. In overall analysis, whereas the PES group showed positive remodeling during follow-up (13.7 +/- 4.2 mm(3)/mm to 14.3 +/- 4.3 mm(3)/mm), the ZES group showed no significant difference (12.7 +/- 3.6 mm(3)/mm to 12.9 +/- 3.5 mm(3)/mm). In subsegment analysis, significant focal positive vessel remodeling was observed in 5% of ZES and 25% of PES cases (p < 0.05).There were different global and focal vessel responses for ZES and PES. Both drug-eluting stents showed a similar incidence of lesions with severe narrowing despite ZES having a moderate increase in neointimal hyperplasia compared with neointimal hyperplasia in PES. There was a relatively lower neointima-free frame ratio in ZES, suggesting a greater extent of neointimal coverage. (The ENDEAVOR IV Clinical Trial: A Trial of a Coronary Stent System in Coronary Artery Lesions; NCT00217269).

Abstract

To evaluate the feasibility of reporter gene imaging in implanted human mesenchymal stem cells (MSCs) in porcine myocardium by using clinical positron emission tomography (PET)-computed tomography (CT) scanning.Animal protocols were approved by the Institutional Administrative Panel on Laboratory Animal Care. Transduction of human MSCs by using different doses of adenovirus that contained a cytomegalovirus (CMV) promoter driving the mutant herpes simplex virus type 1 thymidine kinase reporter gene (Ad-CMV-HSV1-sr39tk) was characterized in a cell culture. A total of 2.25 x 10(6) transduced (n = 5) and control nontransduced (n = 5) human MSCs were injected into the myocardium of 10 rats, and reporter gene expression in human MSCs was visualized with micro-PET by using the radiotracer 9-(4-[fluorine 18]-fluoro-3-hydroxymethylbutyl)-guanine (FHBG). Different numbers of transduced human MSCs suspended in either phosphate-buffered saline (PBS) (n = 4) or matrigel (n = 5) were injected into the myocardium of nine swine, and gene expression was visualized with a clinical PET-CT. For analysis of cell culture experiments, linear regression analyses combined with a t test were performed. To test differences in radiotracer uptake between injected and remote myocardium in both rats and swine, one-sided paired Wilcoxon tests were performed. In swine experiments, a linear regression of radiotracer uptake ratio on the number of injected transduced human MSCs was performed.In cell culture, there was a viral dose-dependent increase of gene expression and FHBG accumulation in human MSCs. Human MSC viability was 96.7% (multiplicity of infection, 250). Cardiac FHBG uptake in rats was significantly elevated (P < .0001) after human MSC injection (0.0054% injected dose [ID]/g +/- 0.0007 [standard deviation]) compared with that in the remote myocardium (0.0003% ID/g +/- 0.0001). In swine, myocardial radiotracer uptake was not elevated after injection of up to 100 x 10(6) human MSCs (PBS group). In the matrigel group, signal-to-background ratio increased to 1.87 after injection of 100 x 10(6) human MSCs and positively correlated (R(2) = 0.97, P < .001) with the number of administered human MSCs.Reporter gene imaging in human MSCs can be translated to large animals. The study highlights the importance of co-administering a "scaffold" for increasing intramyocardial retention of human MSCs.

Abstract

Sirolimus-eluting stents (SES) have been shown to reduce intimal hyperplasia (IH) within the stent. Although angiographic studies have suggested focal distribution of IH, these data are limited by its spatial resolution and the minimal amount of IH. Therefore, the exact distribution pattern of SES IH remains unclear. Ninety-six SIRIUS trial patients who underwent SES (51) or bare metal stent (45) implantation and three-dimensional IVUS at 8 months follow-up were enrolled. Neointimal area (stent-lumen area) was obtained at every 0.5-mm interval throughout the stented segment. The length of each stent with IVUS-detectable neointima was determined and divided by the stented length in each case to normalize the data. Even with IVUS, IH was detectable in very limited SES stented segments (median 8% of total stented length) compared to the diffuse nature of IH within BMS with only 5 stented lesions having segments free from IH. In 25% (13 of 51) of patients, no IH was detectable within whole SES stented segments. In conclusion, SES has reduced not only the total amount of IH, but also limited the distribution. These data suggest that local conditions (heterogeneity of biological responses of particular plaques, pharmacokinetics, or their combination) may play a role in IH following SES implantation.

Abstract

The aim of this study was to evaluate the intraoperative fluorescence imaging (IFI) system in the real-time assessment of graft patency during off-pump coronary artery bypass graft.Intraoperative fluorescence imaging is an intraoperative angiography-like imaging modality using fluorescent indocyanine green excited with laser light. Recently, assessment of graft patency using the IFI system was introduced into clinical use. The feasibility and efficacy of IFI technology in off-pump coronary artery bypass graft has not been systematically compared with other conventional diagnostic modalities.Patients undergoing off-pump coronary artery bypass graft received IFI analysis, intraoperative transit time flowmetry, and postoperative X-ray angiography. In off-line IFI analysis, the graft washout was classified based on the number of heartbeats required for indocyanine green washout: fast washout (15 beats).A total of 507 grafts in 137 patients received IFI analysis. Of all the IFI analyses, 379 (75%) grafts were visualized clearly up to the distal anastomosis. With regard to anastomosis location, anterior location was associated with a higher percentage of fully analyzable images (90%). More than 80% of images were analyzable, irrespective of graft type. Six grafts with acceptable transit time flowmetry results were diagnosed with graft failure by IFI, which required on-site graft revision. All revised grafts' patency was confirmed by post-operative X-ray angiography. Conversely, 21 grafts with unsatisfactory transit time flowmetry results demonstrated acceptable patency with IFI. Graft revision was considered unnecessary in these grafts, and 20 grafts (95%) were patent by post-operative X-ray angiography. Compared with slow washout, fast washout was associated with a higher preoperative ejection fraction, use of internal mammary artery grafts, and anterior anastomosis location.The IFI system enables on-site assessment of graft patency, providing both morphologic and functional information. This technique may help reduce procedure-related, early graft failures in off-pump bypass patients.

Abstract

The coverage, cost, and quality problems of the U.S. health care system are evident. Sustainable health care reform must go beyond financing expanded access to care to substantially changing the organization and delivery of care. The FRESH-Thinking Project (www.fresh-thinking.org) held a series of workshops during which physicians, health policy experts, health insurance executives, business leaders, hospital administrators, economists, and others who represent diverse perspectives came together. This group agreed that the following 8 recommendations are fundamental to successful reform: 1. Replace the current fee-for-service payment system with a payment system that encourages and rewards innovation in the efficient delivery of quality care. The new payment system should invest in the development of outcome measures to guide payment. 2. Establish a securely funded, independent agency to sponsor and evaluate research on the comparative effectiveness of drugs, devices, and other medical interventions. 3. Simplify and rationalize federal and state laws and regulations to facilitate organizational innovation, support care coordination, and streamline financial and administrative functions. 4. Develop a health information technology infrastructure with national standards of interoperability to promote data exchange. 5. Create a national health database with the participation of all payers, delivery systems, and others who own health care data. Agree on methods to make de-identified information from this database on clinical interventions, patient outcomes, and costs available to researchers. 6. Identify revenue sources, including a cap on the tax exclusion of employer-based health insurance, to subsidize health care coverage with the goal of insuring all Americans. 7. Create state or regional insurance exchanges to pool risk, so that Americans without access to employer-based or other group insurance could obtain a standard benefits package through these exchanges. Employers should also be allowed to participate in these exchanges for their employees' coverage. 8. Create a health coverage board with broad stakeholder representation to determine and periodically update the affordable standard benefit package available through state or regional insurance exchanges.

Abstract

Recently, the type 2 diabetes medication, rosiglitazone, has come under scrutiny for possibly increasing the risk of cardiac disease and death. To investigate the effects of rosiglitazone on the diabetic heart, we performed cardiac transcriptional profiling and imaging studies of a murine model of type 2 diabetes, the C57BL/KLS-lepr(db)/lepr(db) (db/db) mouse.We compared cardiac gene expression profiles from three groups: untreated db/db mice, db/db mice after rosiglitazone treatment, and non-diabetic db/+ mice. Prior to sacrifice, we also performed cardiac magnetic resonance (CMR) and echocardiography. As expected, overall the db/db gene expression signature was markedly different from control, but to our surprise was not significantly reversed with rosiglitazone. In particular, we have uncovered a number of rosiglitazone modulated genes and pathways that may play a role in the pathophysiology of the increase in cardiac mortality as seen in several recent meta-analyses. Specifically, the cumulative upregulation of (1) a matrix metalloproteinase gene that has previously been implicated in plaque rupture, (2) potassium channel genes involved in membrane potential maintenance and action potential generation, and (3) sphingolipid and ceramide metabolism-related genes, together give cause for concern over rosiglitazone's safety. Lastly, in vivo imaging studies revealed minimal differences between rosiglitazone-treated and untreated db/db mouse hearts, indicating that rosiglitazone's effects on gene expression in the heart do not immediately turn into detectable gross functional changes.This study maps the genomic expression patterns in the hearts of the db/db murine model of diabetes and illustrates the impact of rosiglitazone on these patterns. The db/db gene expression signature was markedly different from control, and was not reversed with rosiglitazone. A smaller number of unique and interesting changes in gene expression were noted with rosiglitazone treatment. Further study of these genes and molecular pathways will provide important insights into the cardiac decompensation associated with both diabetes and rosiglitazone treatment.

Abstract

The purpose of this study was to evaluate optical coherence tomography (OCT) for detecting small degrees of in-stent neointima (ISN) after stent implantation compared with intravascular ultrasound (IVUS).The importance of detecting neointimal coverage of stent struts has grown with the appreciation of the increased risk for late stent thrombosis after drug-eluting stent (DES) implantation. Intravascular ultrasound, the current standard for evaluating the status of DES, lacks the resolution to detect the initial neointimal coverage. Optical coherence tomography has greater resolution but has not yet been compared with IVUS in vivo with histological correlation for validation.Intravascular ultrasound and OCT were performed with motorized pullback imaging in 6 pigs across 33 stents, 1 month after implantation. Each pig was euthanized, and histological measurements of vessel, stent, and lumen dimensions were performed in 3 sections of each stent. A small degree of ISN was defined as occupying <30% of the stent area measured with histology. The IVUS, OCT, and histological assessment of ISN were compared in matched cross-sections of the stents with a small degree of ISN.Eleven stents had a small degree of ISN (average ISN area: 1.26 +/- 0.46 mm(2), and percent area obstruction: 21.4 +/- 5.2%). Compared with histology, the diagnostic accuracy of OCT (area under the receiver operating characteristic curve [AUC] = 0.967, 95% confidence interval [CI] 0.914 to 1.019) was higher than that of IVUS (AUC = 0.781, 95% CI 0.621 to 0.838).Optical coherence tomography detects smaller degrees of ISN more accurately than IVUS and might be a useful method for identifying neointimal coverage of stent struts after DES implantation.

Abstract

While only few data exist correlating cardiovascular risk factors with volumetric measurements of coronary atheroma burden in patients with coronary artery disease, a recent report using intravascular ultrasound (IVUS) demonstrated independent predictors of atherosclerotic burden in a native coronary artery with relatively mild narrowing (20-50% diameter stenosis by visual estimation). The purpose of this study was to examine whether cardiovascular risk factors can predict atherosclerotic burden at severely narrowing segments (>50% diameter stenosis).Patients who met the criteria (high-quality, automated pull-back IVUS images of severely narrowing segments prior to intervention) were identified from the IVUS database of the Cardiovascular Core Analysis Laboratory at Stanford University. Using commercially available planimetry software, lumen and vessel inside external elastic membrane areas were manually traced at every 0.5-mm interval in diseased segments. Using Simpson's method, vessel, lumen, and plaque (vessel minus lumen) volumes were calculated, and average area was calculated as volume data divided by length. Percent plaque volume was computed as plaque volume divided by vessel volume. Multiple linear regression analysis with backward selection was used to determine the risk factors for atherosclerotic burden.For percent plaque volume, diabetes or hypertension were predictors of more severe disease. For average plaque area, male gender or diabetes were predictors of more severe disease. These variables were also independent predictors in multivariate regression models.Male gender, hypertension, and diabetes are also strong independent predictors of atherosclerotic burden in coronary disease patients, though analyzed segments and disease severity were different.

Abstract

The objective of this study is to evaluate the predictive value of the index of microcirculatory resistance (IMR) in patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI).Despite adequate epicardial artery reperfusion, a number of patients with STEMI have a poor prognosis because of microvascular damage. Assessing the status of the microvasculature in this setting remains challenging.In 29 patients after primary PCI for STEMI, IMR was measured with a pressure sensor/thermistor-tipped guidewire. The Thrombolysis In Myocardial Infarction (TIMI) myocardial perfusion grade, TIMI frame count, coronary flow reserve, and ST-segment resolution were also recorded.The IMR correlated significantly with the peak creatinine kinase (CK) (R = 0.61, p = 0.0005) while the other measures of microvascular dysfunction did not. In patients with an IMR greater than the median value of 32 U, the peak CK was significantly higher compared with those having values 32 U compared with

Abstract

We previously reported that negative remodeling, not plaque progression, correlated with lumen loss during the first year after cardiac transplantation and that cytomegalovirus antibody seropositivity correlated with increased negative remodeling and greater lumen loss. Whether these findings persist between years 1 and 2 after transplantation is unknown.Serial 3-dimensional intravascular ultrasound analysis in the left anterior descending coronary artery was performed in 30 cardiac transplant recipients at year 1 and 2 after transplantation. Vessel, lumen, and plaque area were determined at 0.5-mm axial intervals in the first 50 mm of the left anterior descending coronary artery, and volumes were computed using Simpson's method. Univariate and multivariate regression analyses were performed to identify clinical predictors of change in coronary dimensions.Although mean vessel area did not change (13.6+/-3.4 to 13.4+/-3.3 mm/mm(3), P=0.45), mean plaque area increased (3.4+/-2.3 to 3.8+/-2.2 mm/mm(3), P=0.012), resulting in significant mean lumen area loss (10.3+/-2.5 to 9.6+/-2.3 mm/mm(3), P=0.016). However, the degree of luminal change strongly correlated with the degree of change in vessel size (R=0.81, P<0.0001), but not with change in plaque amount (R=-0.19, P=0.32). In fact, in 57% of the patients who demonstrated lumen loss, negative remodeling contributed more to lumen loss than did plaque progression. Diabetes at 2 years was the only significant independent clinical predictor of plaque progression and lumen loss.Despite significant plaque progression, negative remodeling correlated with coronary lumen loss between years 1 and 2 after cardiac transplantation.

Abstract

Recurrent restenosis may occur after drug-eluting stent implantation for in-stent restenosis (ISR) of bare metal stents (BMSs), especially in areas involving drug-eluting stent gaps.To investigate the details of neointimal progression and luminal narrowing after the treatment of ISR using sirolimus-eluting stents (SESs), serial intravascular ultrasound analysis was performed in 65 patients with ISR at postintervention and at 6-month follow-up. The total stented segment was categorized into 3 compartments: new SES (N), new SES and old BMS overlap (N/O), and old BMS (O). In each of the 190 compartments, serial intravascular ultrasound parameters were analyzed at the cross section of the maximum change in neointimal area (delta neointimal area) from postintervention to follow-up or the minimum lumen area at follow-up if delta neointimal area was 0. Minimum lumen area in each compartment was also investigated serially.At postintervention, lumen area was the smallest in compartment N/O (N 5.8 +/- 1.5, N/O 5.1 +/- 1.3, O 6.0 +/- 1.4 mm2, P = .005). Not only the average of maximum delta neointimal area (N 0.2 +/- 0.4, N/O 0.2 +/- 0.4, O 0.8 +/- 1.0 mm2, P < .0001) but also the frequency of minimum lumen area decreasing from > or = 4.0 mm2 at postintervention to < 4.0 mm2 at follow-up (N 4.0%, N/O 5.1%, O 23.5%, P = .012) was the largest in compartment O.Neointimal progression and consequent luminal narrowing tend to occur where BMS is uncovered with SES in treatment of ISR, even in the absence of an obvious stenosis at postintervention.

Abstract

Cardiac allograft vasculopathy (CAV) is a progressive process involving the epicardial and microvascular coronary systems. The timing of the development of abnormalities in these 2 compartments and the correlation between changes in physiology and anatomy are undefined. The invasive evaluation of coronary artery anatomy and physiology with intravascular ultrasound, fractional flow reserve, coronary flow reserve, and the index of microcirculatory resistance (IMR) was performed in the left anterior descending coronary artery during 151 angiographic evaluations of asymptomatic heart transplant recipients from 0 to >5 years after heart transplantation (HT). There was no angiographic evidence of significant CAV, but during the first year after HT, fractional flow reserve decreased significantly (0.89 +/- 0.06 vs 0.85 +/- 0.07, p = 0.001), and percentage plaque volume derived by intravascular ultrasound increased significantly (15.6 +/- 7.7% to 22.5 +/- 12.3%, p = 0.0002), resulting in a significant inverse correlation between epicardial physiology and anatomy (r = -0.58, p <0.0001). The IMR was lower in these patients compared with those > or =2 years after HT (24.1 +/- 14.3 vs 29.4 +/- 18.8 units, p = 0.05), suggesting later spread of CAV to the microvasculature. As the IMR increased, fractional flow reserve increased (0.86 +/- 0.06 to 0.90 +/- 0.06, p = 0.0035 comparing recipients with IMRs < or =20 to those with IMRs > or =40), despite no difference in percentage plaque volume (21.0 +/- 11.2% vs 20.5 +/- 10.5%, p = NS). In conclusion, early after HT, anatomic and physiologic evidence of epicardial CAV was found. Later after HT, the physiologic effect of epicardial CAV may be less, because of increased microvascular dysfunction.

Abstract

Coronary culprit lesions with plaque rupture (PR) have been treated with different coronary interventions. However, it is unknown whether the presence of PR affects the restenotic process after coronary intervention. One hundred forty-two patients undergoing coronary bare metal stent implantation were enrolled in the present retrospective analysis. Case selection was based on availability of intravascular ultrasound (IVUS) and quantitative coronary angiographic examinations at baseline (before and after intervention) and at follow-up. Serial comparative analyses included qualitative and quantitative features of the culprit lesion and reference segments. PR was defined as an intraplaque cavity in communication with the lumen in the presence of a residual, disrupted cap. Patients were categorized according to the presence/absence of PR. Pre-interventional IVUS detected PR in 54 patients (38%). Baseline patient demographics were similar between the +PR and -PR groups. Quantitative IVUS analysis showed higher rates of positive remodeling and larger vessel and plaque areas in the +PR compared with -PR lesions (p <0.001 for all). At follow-up (7.2 +/- 2.6 months), no statistically significant difference was observed between the 2 groups in quantitative coronary angiographic or IVUS measurements. In conclusion, culprit lesions with PR exhibited larger plaque mass and higher rates of positive remodeling at preintervention IVUS examination. However, when treated with bare metal stents, the absence/presence of preintervention PR was not found to affect the rate or severity of in-stent restenosis in these culprit lesions.

Abstract

Recent sirolimus-eluting stent (SES) studies have suggested higher rates of restenosis in non-left anterior descending (LAD) artery lesions. The aim of this study was to evaluate differential vessel response (LAD versus non-LAD) to SES implantation using serial intravascular ultrasound (IVUS). A total of 94 patients who underwent SES implantation and serial (post-PCI and 8 months) 3-dimensional IVUS were enrolled from our database. Volumetric analysis was performed throughout the stent as well as the adjacent reference segment (up to 5 mm). Volume index (volume/length) was calculated for vessel (VVI), lumen (LVI), and plaque (PVI). Cross-sectional narrowing (CSN) was defined as neointimal area divided by stent area (%). With respect to the in-stent segment, VVI, PVI, and LVI at post-PCI were not significantly different between the LAD (n = 41) and non-LAD (n = 53) lesions. At follow up, however, maximum CSN was significantly greater in the non-LAD lesions (18.3 +/- 15.2% versus 12.2 +/- 10.0%; p = 0.029). At the proximal reference segment, the non-LAD lesions showed a significantly greater LVI decrease than the LAD lesions (p <0.05), primarily due to mild vessel shrinkage observed in the non-LAD lesions. There were no significant differences at the distal reference segment between the LAD and non-LAD lesions. This detailed IVUS analysis suggests that there are minimal differences in the vessel responses following SES implantation. These findings may have potential implications for mechanical and pharmacokinetic properties of next-generation drug-eluting stent technology.

Abstract

Whether gender affects long-term outcomes after bare metal stent implantation remains controversial. The aim of this study was to examine the impact of gender on neointimal hyperplasia in a large cohort of patients after stent implantation using 3-dimensional intravascular ultrasound. Lumen and stent areas were manually traced at 0.5-mm intervals throughout the stented segment. Using Simpson's method, lumen, stent, and neointimal (stent - lumen) volumes were calculated and standardized by stent length. Women were older, presented more often with hyperlipidemia or hypertension, and had smaller reference vessel diameter and mean stent area, compared with men. Although neointimal hyperplasia and neointimal thickness in women were similar to that in men, the percentage of neointimal hyperplasia (neointimal area divided by stent area) was higher in women due to the smaller stent area. After adjusting for stent area, the percentage of neointimal hyperplasia did not differ by gender. In conclusion, the results of this study indicate that neointimal hyperplasia after bare metal stent implantation in women is similar to that seen in men. Despite the similarity in outcome, there are several gender-specific differences in baseline characteristics.

Abstract

Current surgical care and technology has evolved over the centuries from the interplay between creative surgeons and new technologies. As both fields become more specialized, that interplay is threatened. A 2-year educational fellowship is described which teaches both the process and the discipline of medical/surgical device innovation. Multi-disciplinary teams (surgeons, engineers, business grads) are assembled to educate a generation of translators, who can bridge the gap between scientific and technologic advances and the needs of the physician and the patient.

Abstract

Bifurcation lesions remain a challenging lesion subset, even in the era of drug-eluting stents. The aim of this study was to investigate the longitudinal remodeling pattern and cross-sectional plaque location of bifurcation lesions. Seventy-four preintervention intravascular ultrasound studies of left anterior descending bifurcation lesions were analyzed, in which the lesion was located proximal (type A, n=32) or distal (type B, n=42) to the side branch. Vessel area and plaque area at the lesion (VAlesion and PAlesion) and at the reference site (VAreference and PAreference) were measured. The remodeling ratio was defined as VAlesion/VAreference, and the vessel compensation ratio was defined as (VAlesion-VAreference)/(PAlesion-PAreference). The geometric center of the lumen at the lesion site was identified, and the lesion site was divided into circumferential equal arcs to compare the cross-sectional distribution of percentage plaque area (100x[PAlesion/VAlesion]) between the 2 groups. The remodeling ratio (1.03+/-0.15 vs 0.94+/-0.14, p=0.01) and the vessel compensation ratio (0.0+/-0.36 vs -0.37+/-0.61, p<0.01) were significantly greater in type A than in type B lesions. The circumferential distribution pattern of percentage plaque area was significantly different between the groups (analysis of variance p<0.005), with greater percentage plaque area for the vessel wall opposite from the side branch in type B lesions (46.3+/-18.0% vs 54.6+/-15.4%, type A vs type B lesions, p<0.05). In conclusion, these results suggest that a major side branch may affect longitudinal lesion remodeling as well as the circumferential location of atherosclerotic plaque.

Abstract

This study examined whether coronary focal vasospasm occurs in a nonuniform distribution within the coronary tree and whether a longitudinal plaque distribution pattern is present in patients with vasospastic angina using 3-dimensional intravascular ultrasound analysis. Of 121 patients with clinically suspected angina without fixed stenosis in the coronary arteries, vasospasm was provoked in 82 patients with 92 lesions (42 focal, 50 diffuse) by intravenous ergonovine maleate injection. Most focal vasospasms occurred in the proximal third of the coronary arteries (proximal 28, mid 8, distal 6, p <0.01), corresponding to the historical high-risk zones for acute coronary occlusion. More plaque burden also existed in the proximal third of the coronary arteries in patients with focal vasospasm.

Abstract

Previous long-term (>1 year) studies have suggested that saphenous vein bypass grafts (SVGs) undergo vascular remodeling similar to native coronary arteries. However, early morphologic stages of SVG remodeling have not been characterized in vivo.Thirty SVGs were studied 12 months after implantation using an intravascular ultrasound automated pullback system. Intravascular ultrasound images were analyzed between 10 and 60 mm from the tip of the guide. Lumen area (LA), intima area (IA), and vessel area (VA, defined as the area within the outer border of a hypoechoic intimal layer) were computed at 3 cross sections: the minimum LA (MLA) site and the proximal and distal reference sites. Area changes (Delta) were calculated as the MLA site minus the average of the reference sites.In this cohort, 70% of the MLA sites had a smaller VA than the average references. On average, MLA sites had significantly smaller VA (9.7 +/- 2.9 vs 10.7 +/- 3.2 mm2, P < .01) and larger IA (2.5 +/- 2.1 vs 1.2 +/- 1.3 mm2, P < .01) than at the reference sites. The relative contribution of DeltaVA (-1.0 +/- 1.4 mm2) and DeltaIA (1.3 +/- 1.3 mm2) to lumen compromise (-2.3 +/- 1.4 mm2) were 43% and 57%, respectively. On the other hand, simple linear regression analysis revealed a significant positive correlation between DeltaIA and DeltaVA (y = -1.7 + 0.52x, r = 0.50, P < .01).Within the first year, the mechanism of lumen compromise in SVG is a combination of negative remodeling and intimal hyperplasia. Positive remodeling is seen in a minority of cases. However, the direction and extent of remodeling correlated with change in intimal thickness.

Abstract

Diabetes mellitus is an independent predictor of restenosis after percutaneous coronary intervention. The pattern of restenosis after bare metal stent implantation in diabetic patients was examined with 3-dimensional intravascular ultrasound analysis. Lumen and stent were manually traced at every 0.5-mm interval in stented segments. Using Simpson's method, stent, luminal, and neointimal (stent minus lumen) volumes were calculated and average area was calculated as volume data divided by length. To measure the cross-sectional and longitudinal severities of luminal encroachment by the neointima, percent neointimal area (neointimal area divided by stent area) and neointimal hyperplasia 50 (IH50) (defined as percent stent length with percent neointimal area >50%) were calculated. In 278 patients (68 with diabetes and 210 without diabetes), there was a significantly higher percentage of maximal percent neointimal area with significantly longer percent stent length that was severely encroached by the neointima in diabetic patients. Diabetic patients showed a more heterogenous pattern of the neointima after bare metal stenting, resulting in longer high-grade obstruction segments. This may have important implications for stent design and pharmacokinetic properties of next-generation drug-eluting technology for this complex patient subset.

Abstract

To assess whether asymmetric stent expansion affects suppression of neointimal hyperplasia after sirolimus-eluting stent implantation, 64 patients in the SIRolImUS-coated Bx Velocity stent trial who underwent single 18-mm stent implantation and 3-dimensional intravascular ultrasonography at 8-month follow-up were enrolled. To assess the longitudinal stent asymmetric expansion, 2 cross sections with a maximal/minimal stent area were chosen in each patient. To assess for tomographic stent asymmetric expansion, stent eccentricity was determined by dividing the minimum stent diameter by the maximum stent diameter. At the 2 cross sections with a maximal/minimal stent area, a sirolimus-eluting stent reduced neointimal hyperplasia significantly with no interaction between the treatment and stent areas. A sirolimus-eluting stent also significantly reduced neointimal hyperplasia in the concentric and eccentric stent groups.

Abstract

To study the interaction of the sirolimus-eluting stent and vessel margins, we analyzed the intravascular ultrasound parameters in 317 edges of 167 stents having 18 edge stenoses at 8 months of follow-up from the SIRIUS trial. Of the baseline parameters, a larger reference percentage of plaque area and a larger edge stent area/reference minimum lumen area were associated with edge stenosis in the sirolimus-eluting stent cohort compared with the incidence of edge stenosis in the bare metal stent cohort. Thus, full lesion coverage and matching the stented segment properly to the adjacent segment using intravascular ultrasound guidance may improve sirolimus-eluting stent implantation efficacy further.

Abstract

The effect of lesion characteristics on neointimal hyperplasia after sirolimus-eluting stent implantation was examined in 45 patients who underwent successful preinterventional intravascular ultrasound. There were no differences in neointimal hyperplasia between the moderate/severe calcified lesion group (calcium arc >120 degrees ) and the non/mild calcified lesion group or between the positive vessel remodeling group (external elastic membrane area at the minimal lumen area site larger than that at the proximal reference site) and negative vessel remodeling group. No correlation between preinterventional plaque burden and neointimal hyperplasia was found. In patients who have coronary artery disease, sirolimus-eluting stents continue to demonstrate striking suppression of neointimal proliferation, irrespective of lesion characteristics previously associated with greater restenotic risk.

Abstract

We sought to identify the frequency of incomplete stent apposition (ISA) in sirolimus-eluting stents (SES) and clarify its findings and clinical sequelae.Late-acquired ISA has been reported in bare-metal stents (BMS) and brachytherapy and recently in drug-eluting stents. However, the characteristics of late ISA in SES have not been clarified.From the SIRIUS trial, a randomized, multicenter study comparing SES and BMS, serial qualitative intravascular ultrasound (IVUS; at stent implantation and eight-month follow-up) was available in 141 patients (BMS: n = 61; SES: n = 80). The IVUS images were reviewed for the presence of ISA.Incomplete stent apposition at follow-up was observed in 19 patients (BMS: n = 6 [9.8%]; SES: n = 13 [16.3%]; p = NS). Among these, 12 had ISA after intervention and at follow-up (persistent ISA). Late-acquired ISA was seen in the remaining seven cases, all from the SES group (BMS: n = 0; SES: n = 7 [8.7%]; p < 0.05). In late-acquired ISA, there was an increase in external elastic membrane area (after intervention: 16.2 +/- 2.7 m2; follow-up: 18.9 +/- 3.6 mm2; p < 0.05). The location of stent-vessel wall separation was primarily at the stent edges in persistent ISA cases, whereas late-acquired ISA in SES occurred mostly in the mid portion of the stent. There were no negative clinical events reported for any ISA cases at 12-month clinical follow-up.Late ISA was observed in 8.7% of patients after SES implantation. There were no negative clinical events associated with this IVUS finding at 12-month clinical follow-up; however, careful long-term follow-up will be necessary.

Abstract

Several clinical studies are evaluating the therapeutic potential of delivery of various progenitor cells for treatment of injured hearts. However, the actual fate of delivered cells has not been thoroughly assessed for any cell type. We evaluated the short-term fate of peripheral blood mononuclear cells (PBMNCs) after intramyocardial (IM), intracoronary (IC), and interstitial retrograde coronary venous (IRV) delivery in an ischemic swine model.Myocardial ischemia was created by 45 minutes of balloon occlusion of the left anterior descending coronary artery. Six days later, 10(7) 111indium-oxine-labeled human PBMNCs were delivered by IC (n=5), IM (n=6), or IRV (n=5) injection. The distribution of injected cells was assessed by gamma-emission counting of harvested organs. For each delivery method, a significant fraction of delivered cells exited the heart into the pulmonary circulation, with 26+/-3% (IM), 47+/-1% (IC), and 43+/-3% (IRV) of cells found localized in the lungs. Within the myocardium, significantly more cells were retained after IM injection (11+/-3%) compared with IC (2.6+/-0.3%) (P<0.05) delivery. IRV delivery efficiency (3.2+/-1%) trended lower than IM infusion for PBMNCs, but this difference did not reach significance. The IM technique displayed the greatest variability in delivery efficiency by comparison with the other techniques.The majority of delivered cells is not retained in the heart for each delivery modality. The clinical implications of these findings are potentially significant, because cells with proangiogenic or other therapeutic effects could conceivably have effects in other organs to which they are not primarily targeted but to which they are distributed. Also, we found that although IM injection was more efficient, it was less consistent in the delivery of PBMNCs compared with IC and IRV techniques.

Abstract

Adjacent reference vessel response to smaller lumens at stented segments was examined with 3-dimensional intravascular ultrasound analysis. In 128 patients after bare metal stent implantation, minimal lumen area (MLA) within the stent and average lumen area at distal/proximal adjacent reference segments (5 mm) were obtained at baseline and follow-up. In the smaller in-stent MLA group (MLA <3 mm2), lumen area decreased significantly at the distal edge compared with the larger in-stent MLA group (MLA > or =3 mm2), although no significant difference was seen at the proximal edge. In-stent lumen patency may influence vascular responses at adjacent reference segments after bare metal stent implantation.

Abstract

Temperature heterogeneity along the inner surface of an artery may be a surrogate marker of impending plaque rupture and has been associated with an increased likelihood of future coronary events. Initial studies using catheter-based thermographic devices have demonstrated that the changes in temperature are subtle, while the effects of coronary flow on measured temperature have not yet been examined. A novel guidewire-based system (ThermoCoil, Imetrx) designed to measure surface temperature in coronary arteries was used to study the effects of heat source intensity and flow on measured temperature. An in vitro model of a focal, eccentric, heat-generating lesion demonstrated that a guidewire-based system can detect changes in surface temperature with a precision of less than 0.08 degrees C. In this model, temperature measurements increased linearly with source temperature and decreased with increases in flow by an exponent of -0.33 (P < 0.001 for both). Flow rates and heat source properties can significantly influence the measurement and interpretation of thermographic data. The incorporation of 2D thermographic images may contribute further to the characterization of metabolically active plaques likely to cause acute coronary syndromes.

Abstract

The effect of epicardial artery stenosis on myocardial microvascular resistance remains controversial. Recruitable collateral flow, which may affect resistance, was not incorporated into previous measurements.In an open-chest pig model, distal coronary pressure was measured with a pressure wire, and the apparent minimal microvascular resistance was calculated during peak hyperemia as pressure divided by flow, measured either with a flow probe around the coronary artery (R(micro app)) or with a novel thermodilution technique (apparent index of microcirculatory resistance [IMR(app)]). These apparent resistances were compared with the actual R(micro) and IMR after the coronary wedge pressure and collateral flow were incorporated into the calculation. Measurements were made at baseline (no stenosis) and after creation of moderate and severe epicardial artery stenoses. In 6 pigs, 189 measurements of R(micro) and IMR were made under the various epicardial artery conditions. Without consideration of collateral flow, R(micro app) (0.43+/-0.12 to 0.46+/-0.10 to 0.51+/-0.11 mm Hg/mL per minute) and IMR(app) (14+/-4 to 17+/-7 to 20+/-10 U) increased progressively and significantly with increasing epicardial artery stenosis (P<0.001 for both). With the incorporation of collateral flow, neither R(micro) nor IMR increased as a result of increasing epicardial artery stenosis.After collateral flow is taken into account, the minimum achievable microvascular resistance is not affected by increasing epicardial artery stenosis.

Abstract

Delivery of angiogenic factors to ischemic myocardium remains a practical challenge. We evaluated the efficiency and efficacy of delivery of fibroblast growth factor-2 (FGF-2) protein via high-pressure retrograde injection into the anterior interventricular vein (AIV) in a porcine model of chronic myocardial ischemia. Labeled FGF-2 protein was delivered to the myocardium of three pigs via the AIV and the left anterior descending (LAD) coronary artery in three others. At 1 hr, the amount of protein in the left ventricle and the LAD region was quantified. Copper stents were implanted in the LAD of 25 pigs, resulting in chronic myocardial ischemia. At 4 weeks, microsphere-derived myocardial blood flow was assessed at rest and during pacing. In eight pigs (AIV FGF), FGF-2 protein (6 microg/kg) was delivered via high-pressure retrograde injection into the AIV. Six pigs (intracoronary FGF) received the same amount of FGF-2 by intracoronary delivery. Five pigs (AIV saline) received a placebo injection into the AIV and six pigs (control) served as controls. Four weeks later, myocardial blood flow was reassessed. At 1 hr, significantly more FGF remained in the left ventricle (1.3 vs. 0.82 microg; P < 0.04) and in the LAD region (1.2 vs. 0.64 microg; P = 0.03) after AIV compared to intracoronary delivery. Four weeks after treatment, resting LAD blood flow (normalized to right ventricular flow) improved slightly in the AIV FGF and intracoronary FGF arms (1.32-1.37 for both; P = 0.11), while it decreased significantly in the AIV saline (1.32-1.23; P = 0.02) and the control arms (1.32-1.19; P = 0.0004). Pacing LAD blood flow decreased significantly in the control arm (1.30-1.23; P < 0.05), but did not change significantly in the other three arms. High-pressure retrograde injection into the AIV may represent an efficient and effective means for delivering angiogenic factors to ischemic myocardium.

Abstract

The use of directional coronary atherectomy (DCA) in current practice has been limited. The SilverHawk System is a newly developed plaque excision device that aims to overcome the drawbacks of prior DCA platforms. The device was evaluated in a porcine coronary model and in a series of patients. Procedural variables along with outcomes were reviewed. Quantitative angiography (QCA) was performed and excised tissue fragments were weighed and examined histologically. In porcine cases, pretreatment MLD increased from 0.51 +/- 0.26 to 2.36 +/- 0.59 mm postdebulking and 19.9 +/- 7.6 mg of tissue was retrieved. In human cases, pretreatment MLD increased from 0.8 +/- 0.4 to 2.2 +/- 0.5 mm postdebulking and 15.2 +/- 7.8 mg of tissue was retrieved without complications. These data show that the SilverHawk System may offer significant utility in treating a wide variety of complex coronary lesions.

Abstract

Late incomplete stent apposition was observed in 2.4% of the 412 stented segments studied by serial intravascular ultrasound analyses. Most of these phenomena and all late vessel expansions with incomplete stent apposition developed in vessels in which lesions were treated by atherectomy before stenting, suggesting a potential association between mechanical injury from debulking and these phenomena.

Abstract

Current treatment for acute myocardial infarction (AMI) focuses on reestablishing blood flow (reperfusion). Paradoxically, reperfusion itself may cause additional injury to the heart. We previously found that delta-protein kinase C (deltaPKC) inhibition during simulated ischemia/reperfusion in isolated rat hearts is cardioprotective. We focus here on the role for deltaPKC during reperfusion only, using an in vivo porcine model of AMI.An intracoronary application of a selective deltaPKC inhibitor to the heart at the time of reperfusion reduced infarct size, improved cardiac function, inhibited troponin T release, and reduced apoptosis. Using 31P NMR in isolated perfused mouse hearts, we found a faster recovery of ATP levels in hearts treated with the deltaPKC inhibitor during reperfusion only.Reperfusion injury after cardiac ischemia is mediated, at least in part, by deltaPKC activation. This study suggests that including a deltaPKC inhibitor at reperfusion may improve the outcome for patients with AMI.

Abstract

Thermodilution coronary flow reserve (CFRthermo) is a new technique for invasively measuring coronary flow reserve (CFR) with a coronary pressure wire and is based on the ability of the pressure transducer to also measure temperature changes. Whether CFRthermo correlates well enough with absolute flow-derived CFR (CFRflow) to replace Doppler wire-derived CFR (CFRDoppler) remains unclear.In an open-chest pig model, CFRthermo was measured in the left anterior descending (LAD) artery and compared with CFRDoppler and CFRflow, measured with an external flow probe placed around the LAD. In 9 pigs, CFR was measured simultaneously by all 3 means in the normal LAD and after creation of an epicardial LAD stenosis. To determine the added effect of microvascular disease, measurements of flow reserve were also performed after disruption of the coronary microcirculation with embolized microspheres. Intracoronary papaverine (20 mg) was used to induce hyperemia. In a total of 61 paired measurements, CFRthermo correlated strongly with the reference standard CFRflow (r=0.85, P<0.001). CFRDoppler correlated less well with CFRflow (r=0.72, P<0.001). Bland-Altman analysis showed a closer agreement between CFRthermo and CFRflow.CFRthermo correlates better with CFRflow than does CFRDoppler.

Abstract

The utility of measuring fractional flow reserve (FFR) to assess cardiac transplant arteriopathy has not been evaluated. Measuring coronary flow reserve (CFR) as well as FFR could add information about the microcirculation, but until recently, this has required two coronary wires. We evaluated a new method for simultaneously measuring FFR and CFR with a single wire to investigate transplant arteriopathy.In 53 cases of asymptomatic cardiac transplant recipients without angiographically significant coronary disease, FFR and thermodilution-derived CFR (CFRthermo) were measured simultaneously with the same coronary pressure wire in the left anterior descending artery and compared with volumetric intravascular ultrasound (IVUS) imaging. The average FFR was 0.88+/-0.07; in 75% of cases, the FFR was less than the normal threshold of 0.94; and in 15% of cases, the FFR was < or =0.80, the upper boundary of the gray zone of the ischemic threshold. There was a significant inverse correlation between FFR and IVUS-derived measures of plaque burden, including percent plaque volume (r=0.55, P<0.0001). The average CFRthermo was 2.5+/-1.2; in 47% of cases, CFRthermo was < or =2.0. In 14%, the FFR was normal (> or =0.94) and the CFR was abnormal (<2.0), suggesting predominant microcirculatory dysfunction.FFR correlates with IVUS findings and is abnormal in a significant proportion of asymptomatic cardiac transplant patients with normal angiograms. Simultaneous measurement of CFR with the same pressure wire, with the use of a novel coronary thermodilution technique, is feasible and adds information to the physiological evaluation of these patients.

Abstract

Intravascular brachytherapy may cause "exaggerated" vessel remodeling with late incomplete apposition in segments that have little disease, which are exposed to higher radiation doses. The long-term clinical impact of this finding is unclear.

Abstract

A relatively simple, invasive method for quantitatively assessing the status of the coronary microcirculation independent of the epicardial artery is lacking.By using a coronary pressure wire and modified software, it is possible to calculate the mean transit time of room-temperature saline injected down a coronary artery. The inverse of the hyperemic mean transit time has been shown to correlate with absolute flow. We hypothesize that distal coronary pressure divided by the inverse of the hyperemic mean transit time provides an index of microcirculatory resistance (IMR) that will correlate with true microcirculatory resistance (TMR), defined as the distal left anterior descending (LAD) pressure divided by hyperemic flow, measured with an external ultrasonic flow probe. A total of 61 measurements were made in 9 Yorkshire swine at baseline and after disruption of the coronary microcirculation, both with and without an epicardial LAD stenosis. The mean IMR (16.9+/-6.5 U to 25.9+/-14.4 U, P=0.002) and TMR (0.51+/-0.14 to 0.79+/-0.32 mm Hg x mL(-1) x min(-1), P=0.0001), as well as the % change in IMR (147+/-66%) and TMR (159+/-105%, P=NS versus IMR % change), increased significantly and to a similar degree after disruption of the microcirculation. These changes were independent of the status of the epicardial artery. There was a significant correlation between mean IMR and TMR values, as well as between the % change in IMR and % change in TMR.Measuring IMR may provide a simple, quantitative, invasive assessment of the coronary microcirculation.

Abstract

We sought to document whether a physiologic change in gender has any effect on coronary arterial size.The coronary arteries are smaller in women, even after correction for body surface area (BSA). These differences may contribute to adverse clinical outcomes after coronary artery bypass graft surgery and myocardial infarction in women. In male and female transsexuals, pharmacologic doses of estrogens and androgens significantly influence vascular diameter. Thus, gender differences in the coronary vasculature may be a reflection of the hormonal environment.In 86 patients who had undergone orthotopic heart transplantation, serial intravascular ultrasound studies of the proximal left anterior descending coronary artery (LAD) were analyzed. Changes in vessel area (VA) over the first or second post-transplant year were recorded, and comparisons were made between donor hearts that were transplanted in a patient of the same gender and those that were transplanted in a patient of the opposite gender.Vessel area of the proximal LAD increased over time in all patient groups. In hearts transplanted within the same gender and in male donor hearts transplanted to female recipients, the change was small and not significant. However, in hearts transplanted from female donors to male recipients, there was a substantial and highly significant increase in LAD VA (median 16.13 to 17.88 mm(2); p = 0.01). This increase was not explained by confounding due to changes in BSA or left ventricular wall thickness.This pattern of arterial remodeling early after heart transplantation supports a link between host gender and coronary arterial size.

Abstract

Most patients come to the catheterization laboratory without prior functional tests, which makes the cost-effective treatment of patients with intermediate coronary lesions a practical challenge.We developed a decision model to compare the long-term costs and benefits of 3 strategies for treating patients with an intermediate coronary lesion and no prior functional study: 1) deferring the decision for percutaneous coronary intervention (PCI) to obtain a nuclear stress imaging study (NUC strategy); 2) measuring fractional flow reserve (FFR) at the time of angiography to help guide the decision for PCI (FFR strategy); and 3) stenting all intermediate lesions (STENT strategy). On the basis of the literature, we estimated that 40% of intermediate lesions would produce ischemia, 70% of patients treated with PCI and 30% of patients treated medically would be free of angina after 4 years, and the quality-of-life adjustment for living with angina was 0.9 (1.0 = perfect health). We estimated the cost of FFR to be 761 dollars, the cost of nuclear stress imaging to be 1093 dollars, and the cost of medical treatment for angina to be 1775 dollars per year. The extra cost of splitting the angiogram and PCI as dictated by the NUC strategy was 3886 dollars by use of hospital cost-accounting data. Sensitivity and threshold analyses were performed to determine which variables affected our results.The FFR strategy saved 1795 dollars per patient compared with the NUC strategy and 3830 dollars compared with the STENT strategy. Quality-adjusted life expectancy was similar among the 3 strategies (NUC-FFR = 0.8 quality-adjusted days, FFR-STENT = 6 quality-adjusted life days). Compared with the FFR strategy, the NUC strategy was expensive (>800,000 dollars per quality-adjusted life year gained). Both screening strategies were superior to (less cost, better outcomes) the STENT strategy. Sensitivity analysis indicated that the NUC strategy would only become attractive (<50,000 dollars/quality-adjusted life years compared with FFR) if the specificity of nuclear stress imaging was >25% better than FFR. Our results were not altered significantly by changing the other assumptions.In patients with an intermediate coronary lesion and no prior functional study, measuring FFR to guide the decision to perform PCI may lead to significant cost savings compared with performing nuclear stress imaging or with simply stenting lesions in all patients.

Abstract

Treatment with antiproliferative drugs via coated stents appears to be a promising approach to both mechanically remodel target lesions and biologically reduce neointimal hyperplasia. Drug-eluting stents can maximize local drug effects and minimize the potential for systemic toxic effects. The purpose of this review is to describe the effects of a lipophilic microtubular inhibitor, paclitaxel, a strong antiproliferative agent under clinical investigation, and to define the vascular response to taxol-based eluting stents by intravascular ultrasound.

Abstract

We investigated whether neointimal regrowth is related to the mechanism of acute lumen gain during the treatment of in-stent restenosis (ISR) lesions both with and without adjunct intravascular brachytherapy. From the WRIST (Washington Radiation for In-Stent Restenosis Trial) cohort, 54 ISR patients ((192)Ir, 29; placebo, 25) were treated with nonrepeat stenting percutaneous interventions (excimer laser, rotational atherectomy, and/or balloon angioplasty) prior to (192)Ir or placebo therapy. Using Simpson's method, serial volumetric intravascular ultrasound (IVUS) analyses (pre- and posttreatment and 6-month follow-up) were analyzed to obtain stent, lumen, and intimal hyperplasia (IH) volumes that were then adjusted for stent length to create stent, lumen, and IH volume indexes. In the placebo group, the acute reduction of neointima (1.6 +/- 1.4 mm(3)/mm) was counteracted by intimal regrowth (2.1 +/- 1.7 mm(3)/mm). The amount of intimal regrowth correlated directly with the intimal reduction due to the intervention (r = 0.76; P < 0.001), but not with the amount of additional stent expansion. In the (192)Ir-treated group, intimal regrowth was significantly less than in the placebo group (-0.3 +/- 0.1 vs. 2.1 +/- 1.7 mm(3)/mm; P < 0.001) despite a similar initial intimal reduction (1.3 +/- 0.9 vs. 1.6 +/- 1.4 mm(3)/mm; P = NS). No correlation was found between intimal reduction at the time of the procedure and intimal regrowth in the (192)Ir group. In this study, neointimal regrowth following treatment of ISR lesions correlates directly with the extent of acute intimal volume reduction, but not with the extent of additional stent expansion. This relation is not seen in ISR segments treated with radiation, where intimal regrowth is substantially inhibited.

Abstract

Deep vessel wall injury is believed to affect vessel dimension following coronary intervention. The cutting balloon is designed to treat coronary artery stenoses with dilatation and surgical incisions, thereby reducing excess vessel injury. This study examines the effect of deep vessel wall injury on acute and late coronary arterial response after cutting balloon angioplasty. Serial volumetric intravascular ultrasound (IVUS) analyses were performed in 63 lesions treated with cutting balloon angioplasty alone. Before intervention, the longitudinal range of the lesion segment that included the smallest lumen area (LA) was determined as LA <4 mm(2) and/or LA stenosis >60%. The exact corresponding site at postintervention and follow-up was aligned using peri- and intravascular landmarks. Average vessel area (VA), plaque area (PA), and LA were measured. Lesion segments were categorized as with or without deep vessel wall injury, which was defined as the presence of plaque/vessel wall fracture extending to the sonolucent (medial) layer. Before intervention, the lesion vessel size of deep injury group was smaller than that of the nondeep injury group (p <0.05 for average VA and PA), whereas average lesion LA, lesion length, and reference vessel size did not differ. Immediately after cutting balloon angioplasty, the deep injury group showed a significant increase in VA (p <0.0001) and a lesser decrease in PA (p <0.01) compared with the nondeep injury group. During follow-up, the increase of VA tended to be greater in the deep injury group than in the nondeep injury group (p = 0.06), whereas the change of PA did not differ. Consequently, LA decrease was less in the deep injury group than in the nondeep injury group (p <0.05). From these results, it is suggested that deep vessel wall injury tends to occur in lesions with relatively small size and such lesions show favorable vessel response after cutting balloon angioplasty.

Abstract

The Helixcision system is a novel 6 Fr-compatible catheter designed to debulk tissue for in-stent restenosis lesions. The purpose of this study was to determine the efficacy and feasibility of this new system for removing neointimal hyperplasia. A total of 32 in-stent restenosis lesions in 32 patients were treated with helixcision followed by balloon angioplasty. Debulking efficacy was assessed with serial baseline intravascular ultrasound (IVUS) in a subset of 18 lesions. To investigate longitudinal efficacy, 3D analysis was also performed in 12 lesions with automated pullback to calculate average cross-sectional areas across the stent. Prior to procedure, the angiographic reference diameter was 2.60 +/- 0.46 mm. Immediately after procedure, minimum lumen diameter improved from 0.84 +/- 0.33 to 2.19 +/- 0.41 mm (P < 0.0001). IVUS showed a significant reduction of intimal area (IA) after helixcision (from 4.95 +/- 2.04 to 2.88 +/- 1.48 mm(2); P < 0.001). Adjunctive balloon angioplasty further improved lumen area (LA) mainly by stent expansion rather than IA reduction at the site of minimum lumen area. The degrees of IA reduction and LA improvement were closely similar in volumetric analysis. Thirty-day and 6-month clinical follow-up were available in 97% (n = 31) and 72% (n = 23) of the enrolled patients, respectively. At 30-day follow-up, no major adverse cardiac event was reported except for periprocedural CK elevation in two patients (6%). Target legion revascularization within 6 months was performed in six patients (26%). Preliminary results of helixcision indicate that this system is safe and feasible for the treatment of in-stent restenosis. The concordant results between 2D and 3D IVUS analyses suggest that this unique technology can achieve uniform longitudinal debulking throughout the stent. The long-term outcomes appeared to be favorable, considering the relatively diffuse lesion morphology.

Abstract

Observations from previous intracoronary radiation therapy trials noted a considerable discrepancy between the prescribed radiation dose and the dose actually delivered. The aims of this study were to investigate the effect of actual delivered dose on vascular changes and to test the appropriateness of the current dose prescription.Serial volumetric intravascular ultrasound (IVUS) analysis was performed in 30 in-stent restenosis cases treated with a 40-mm (90)Sr/Y source train. The fixed dose was prescribed at 2 mm from the centerline of the source train (18.4 Gy at 2 mm for reference diameter < or =3.35 mm and 23 Gy for diameter > or =3.36 mm). Only stent segments with full radiation coverage and device injury were enrolled and divided into 2-mm-long subsegments (n=202). D(S90)EEM (the minimum dose absorbed by 90% of the external elastic membrane surface) was calculated as the delivered dose corresponding to each segment, assuming that the radiation catheter occupied the same position in the vessel as the IVUS catheter. Mean D(S90)EEM of 23.5+/-5.82 Gy (range 12.3 to 41.7 Gy) was delivered to these subsegments. Overall, intimal hyperplasia volume remained constant from postintervention to follow-up (2.23+/-1.10 to 2.32+/-1.09 mm3/m; P=NS). Regression analysis revealed there was no correlation between delivered dose intensity and changes in intimal hyperplasia volume. No particular dose-dependent complications were appreciated in this delivered dose range.The current dose-prescription protocol of (90)Sr/Y radiation to native in-stent restenosis lesions may provide substantial inhibition of neointimal reproliferation regardless of the actual delivered dose intensity.

Abstract

Catheter-based vascular interventions have been in development worldwide for several decades, leading to remarkable progress in device technology. Mechanical interventional devices, such as angioplasty balloons, atherectomy devices, and stents, were invented and have contributed greatly to the treatment of atherosclerotic vascular stenosis. However, mechanical approaches do not effectively prevent subsequent intimal growth. Recently, several biological approaches, including radiation therapy and drug-eluting stents, have shown striking inhibition of intimal growth. These significant results are likely to change the treatment strategy in the field of interventional cardiology. Furthermore, additional catheter-based technologies for vascular interventions are presently being evaluated. These latest technologies designed to prevent intimal proliferation include intravascular sonotherapy, cryotherapy, photoangioplasty, and soft X ray. To date, intravascular sonotherapy has proven its efficacy in animal studies and safety in human studies. Cryotherapy, the application of cold thermal energy during angioplasty, enhances the acute effects of conventional dilation while decreasing the likelihood of restenosis. Photoangioplasty has a unique property based on its selective mechanism of action to treat atheromatous plaque. Soft X ray systems provide convenient device handling and well-controlled radiation dose. Some of these technologies may play an important role in vascular interventions in the near future.

Abstract

Inhibition of neointimal tissue growth has been demonstrated in preliminary human feasibility studies with a stent-based polymer sleeve delivering 7-hexanoyltaxol. The Study to COmpare REstenosis rate between QueST and QuaDS-QP2 (SCORE) trial is a human, randomized, multicenter trial comparing 7-hexanoyltaxol (QP2)-eluting stents (qDES) with bare metal stents (BMS) in the treatment of de novo coronary lesions. The purpose of this substudy was to evaluate the acute expansion property and long-term neointimal responses of qDES compared with BMS as assessed by intravascular ultrasound (IVUS).A total of 122 (qDES 66, BMS 56) patients were enrolled into the IVUS substudy. All IVUS images (immediately after the procedure and at 6-month follow-up) were analyzed at an independent core laboratory in a blind manner. At baseline, qDES achieved stent expansion similar to BMS. At follow-up, qDES showed reduced neointimal growth by 70% at the tightest cross section and by 68% over the stented segment (P<0.0001 for both), resulting in a significantly larger lumen in qDES than in BMS. Unlike intracoronary brachytherapy, there was no evidence of negative edge effects, unhealed dissections, or late stent-vessel wall malapposition over the stented and adjacent references segments in either group.Detailed IVUS analysis revealed that qDES had comparable acute mechanical and superior long-term biological effects to BMS. Although the long-term benefits and limitations of this technology require further investigation, the reduction in neointimal thickenings demonstrated that local delivery of 7-hexanoyltaxol through polymer sleeves augments conventional mechanical treatment of atherosclerotic disease.

Abstract

Arterial remodeling has been shown to be responsible for lumen narrowing after nonstent interventions.To examine the impact of deep vessel wall injury (DI) after balloon angioplasty on the subsequent vessel remodeling process, we performed serial intravascular ultrasound (IVUS) analysis in 47 native coronary artery lesions that underwent balloon angioplasty. An IVUS study was performed before and after balloon angioplasty and repeated at follow-up. Vessel and lumen area were measured at the narrowest site before intervention. Plaque area was calculated as vessel area minus lumen area. DI was defined as the presence of plaque/vessel wall fracture deep in the medial layer (sonolucent zone by IVUS) after angioplasty.After angioplasty, DI was present in 18 (38%, DI group) and absent in 29 (62%, non-DI group) of lesions. During follow-up, changes in vessel area in the DI group were significantly larger than in the non-DI group (P =.007). There were no significant differences in changes in plaque area. A trend toward greater late lumen loss was observed in the non-DI group (P =.05). In the DI group, changes in lumen area correlated better with changes in vessel area (r = 0.81, P

Abstract

Radiofrequency intravascular ultrasound (IVUS-RF) analysis, as an extension of conventional IVUS imaging, may provide more accurate plaque discrimination. Thirty-two autopsy atherosclerotic coronary arteries were investigated. Corresponding sectors in different plaques were matched by histologic and RF analysis. Histologic analysis utilized the American Heart Association plaque classification. The backscattered ultrasound RF signal was analyzed by fast-Fourier transform, providing the underlying frequency components of its power spectrum. The normalized backscattered signal power (in decibels [dB]) for frequencies between 15.3 and 40.3 MHz was then measured for plaque discrimination. Advanced/complicated plaque types showed a higher signal power at all frequencies than early/intermediate lesion types (p <0.001 to p = 0.005). Discrimination of advanced/complicated lesion types was best at 15.3 MHz, with a cut-off point of 2.5 dB (sensitivity 93%, specificity 79%), and second best at 17.6 MHz (sensitivity 87%, specificity 71%, cut-off point 1.9 dB). With conventional IVUS, plaque discrimination was weaker; the best sensitivity for diagnosing early/intermediate lesion types was reached for "soft plaque" (sensitivity 63%, specificity 73%). Compared with conventional IVUS, IVUS-RF can discriminate between advanced/complicated and early/intermediate coronary atherosclerotic lesions with relatively high sensitivity and specificity in vitro.

Abstract

Re-stenting of in-stent restenosis (ISR) improves acute angiographic results. Methods and Results- Volumetric intravascular ultrasound analysis was performed in 70 ISR lesions that received either placebo (n=36) or (192)Ir radiation (n=34). ISR lesions treated by re-stenting were divided into 3 groups: old stent not re-stented (A), old/new stent overlap (B), and new stent only (C). ISR lesions treated without re-stenting were categorized as D. In placebo patients, postintervention lumen volume index (LVI) was significantly greater in re-stented segments B and C than in non-re-stented segment A (P<0.05).At follow-up, however, LVI was similar in all 4 segments secondary to the increased intimal hyperplasia (IH) reaccumulation within the re-stented segments. In patients treated with (192)Ir radiation, LVI was maintained from baseline to follow-up only in non-re-stented segments A and D. Conversely, there was a significant decrease in LVI in re-stented segments B and C (P<0.05). Qualitatively, 79% of patients in the irradiated group had stent struts with undetectable neointimal versus only 27% in the placebo group (P<0.001). Coefficient of variation of IH reaccumulation was greater in re-stented segments of (192)Ir patients (B=57.3% and C=58.9%) than in re-stented segments in placebo patients (B=27.3% and C 26.8%) and non-re-stented segments in irradiated patients.Additional lumen gain from re-stenting ISR lesions is counteracted by exaggerated neointimal proliferation in placebo patients. Maximum effectiveness and safety of radiation can be achieved for ISR lesions when treated without re-stenting. Thus, regardless of supplementary intravascular brachytherapy, repeat stenting strategies provided little long-term advantage.

Abstract

To determine whether intramural administration of L-arginine reduces intimal thickening after optimal Palmaz-Schatz stent deployment in humans, 50 patients with native coronary artery disease who received a single Palmaz-Schatz stent were enrolled in this pilot study. Patients were randomized into 2 treatment groups: an L-arginine group (n = 25) and a saline group (n = 25). After stent deployment, L-arginine (600 mg/6 ml) or saline (6 ml) was locally delivered via the Dispatch catheter (Scimed) over 15 minutes. Serial angiography and intravascular ultrasound examinations (motorized pull-back at 0.5 mm/s) were performed before and after the procedure, and at 6-month follow-up. Measurements of stent area, lumen area, and neointimal area were computed within the stents at 1-mm intervals, by technicians who were blinded to the treatment assignment. Using Simpson's rule, stent, plaque, and lumen volumes, neointimal volume within the stent, and percent neointimal volume were measured before and after the procedure, and at 6-month follow-up. The 6-month volume data in quantitative coronary ultrasound showed that neointimal volume in the L-arginine group was significantly less than in the saline group (25 vs 39 mm(3); p = 0.049). Similarly, percent neointimal volume was significantly less in the L-arginine group at 6-month follow-up (17 +/- 13% vs 27 +/- 21%; p = 0.048). Thus, these results showed that local delivery of L-arginine reduces in-stent neointimal hyperplasia in humans, indicating that this approach may be a novel strategy to prevent in-stent restenosis.

Abstract

Acute myocardial infarction is a frequent cause of sudden death, and is typically initiated by the rupture of coronary artery plaques. The likelihood and severity of rupture are influenced by the plaque structures and components. Radiofrequency (RF) intravascular ultrasound (US) (IVUS-RF) measurements extend current IVUS imaging techniques and may eventually enable the in vivo identification of these features. However, IVUS-RF measurements are affected by the transducer's instantaneous position in the vessel. Specifically, backscattered intensity (BI) decreases as either the distance between the tissue and the transducer increases, or as the beam's angle of incidence on the tissue increases. IVUS-RF data were acquired from seven disease-free coronary arteries in vitro. The 0-dB level for BI was defined as the peak intensity of the reflection from a stainless-steel flat reflector at each distance. The baseline BI measured in adventitial tissue was -32.5 dB (at 0 degrees, 0 mm) with angle and distance dependencies of -0.172 dB/ degrees and -3.37 dB/mm. In contrast, the BI from combined intima and media was -38.2 dB with dependencies of -0.111 dB/ degrees and -4.46 dB/mm (p < 0.05 for all three parameters). Acknowledging and compensating for these effects may allow IVUS-RF to develop into a rapidly deployable tool for the clinical detection of vulnerable plaques and to monitor coronary artery disease progression and regression.

Abstract

To investigate whether intravascular ultrasound provides additional information regarding the prediction of stent thrombosis, a retrospective multicentre registry was designed to enrol patients with stent thrombosis following stent deployment under ultrasound guidance.A total of 53 patients were enrolled (mean age 61+/-9 years) with stable angina (43%), unstable angina (36%), and post-infarct angina (21%) who underwent intracoronary stenting. The majority had balloon angioplasty alone prior to stenting (94%) with 6% also undergoing rotational atherectomy. The indication for stenting was elective (53%), suboptimal result (32%) and bailout (15%). There were 1.6+/-0.8 stents/artery with 87% undergoing high-pressure dilatation (> or =14 atmospheres). The minimum stent area was 7.7+/-2.8 mm(2)with a mean stent expansion of 81.5+/-21.9%. Overall, 94% of cases demonstrated one abnormal ultrasound finding (stent under-expansion, malapposition, inflow/outflow disease, dissection, or thrombus). Angiography demonstrated an abnormality in only 32% of cases (chi-square=30.0, P<0.001). Stent thrombosis occurred at 132+/-125 h after deployment. Myocardial infarction occurred in 67% and there was an overall mortality of 15%.On comparison with angiography, the vast majority of stents associated with subsequent thrombosis have at least one abnormal feature by intravascular ultrasound at the time of stent deployment.

Abstract

The purpose of this study was to assess the impact of pre-intervention arterial remodeling on subsequent vessel behavior following balloon angioplasty.Positive arterial remodeling before intervention has been shown to have a negative impact on the clinical outcome after nonstented coronary interventional procedures. However, the mechanism of interventions in coronary vessel geometry over time is less well characterized.Serial (pre-, post- and follow-up) intravascular ultrasound analysis was performed in 46 native coronary lesions. Positive remodeling (PR) was defined as vessel area (VA) at the target lesion greater than that of average reference segments. Intermediate or negative remodeling (IR/NR) was defined as VA at the target lesion less than or equal to that of average reference segment. Remodeling index was defined as VA at the target lesion site divided by that of average references.Pre-interventional PR and IR/NR were present in 21 (46%) and 25 (54%) of 46 patients, respectively. At follow-up, the change in plaque area was similar between the two groups (1.3 +/- 2.1 vs. 1.2 +/- 2.1 mm(2), p = 0.840). Lesions with PR showed a significantly smaller change in VA than those with IR/NR (-0.2 +/- 2.5 vs. 1.4 +/- 2.3 mm(2), p = 0.03). As a result, late lumen loss was significantly larger in lesions whose pre-intervention configuration exhibited PR (-1.5 +/- 1.8 vs. 0.2 +/- 1.6 mm(2), p = 0.002).Lesions with PR appear to have less capacity to compensate for further plaque growth after balloon angioplasty and thus show a proportional increase in late lumen loss. This may in part explain the less favorable clinical outcomes of positively remodeled lesions.

Abstract

Adjunctive balloon dilatation strategy has been shown to improve optimal stent deployment. As improvements in current stent designs evolve, less adjunctive balloon dilatation may be needed. However, few data currently exist to support this practice. We evaluated 88 native coronary lesions treated with single stent implantation (Nir, Tristar or S670). Serial intravascular ultrasound was performed after successful stent deployment and again after adjunctive balloon dilatation. To investigate further the precise expansion characteristics of the stents, serial volumetric intravascular ultrasound analyses were performed in 40 patients with automated pullback. After adjunctive balloon dilatation, minimal stent area increased significantly, from 6.4 +/- 2.1 to 7.4 +/- 2.2 mm(2) (p <0.001). Volumetric analysis showed a corresponding increase in stent volume index (6.6 +/- 1.8 to 7.5 +/- 2.0 mm(3)/mm, p <0.001). In the analysis of cross sections at 0.5-mm axial intervals, the percentage of cross sections, where stent area was > or =80% of the average reference lumen area, increased from 51% to 78% (p <0.001). Similarly, the percentage of cross sections, where stent area was > or =90% of the average reference lumen area, increased from 29% to 56% (p <0.001) with postdilatation. Postdeployment high- pressure balloon dilatation improved minimal stent area and volumetric expansion throughout the stented segment.

Abstract

Determination of fractional flow reserve (FFR) has been proposed as a means to assess stent deployment. In this prospective, multicenter trial, we evaluate the use of FFR to optimize stenting by comparing it with standard intravascular ultrasound (IVUS) criteria.Eighty-four stable patients with isolated coronary lesions underwent coronary stent deployment starting at 10 atm and increased serially by 2 atm until the FFR was >/=0.94 or 16 atm was achieved. IVUS was then performed. FFR was measured with a coronary pressure wire with intracoronary adenosine to induce hyperemia. The diagnostic characteristics of an FFR <0.94 to predict suboptimal stent expansion by IVUS, defined in both absolute and relative terms, were calculated. Over a range of IVUS criteria, the highest sensitivity, specificity, and predictive accuracy of FFR were 80%, 30%, and 42%, respectively. Receiver operator characteristic analysis defined an optimal FFR cut point at >/=0.96; at this threshold, the sensitivity, specificity, and predictive accuracy of FFR were 75%, 58%, and 62%, respectively (P=0.03 for comparison of predictive accuracy, P=0.01 for concordance between FFR and IVUS). The negative predictive value was 88%. Significantly better diagnostic performance was achieved in a subgroup that received higher doses (>30 microgram) of intracoronary adenosine during pressure measurements, suggesting that FFR might be overestimated in the other group.A fractional flow reserve <0.96, measured after stent deployment, predicts a suboptimal result based on validated intravascular ultrasound criteria; however, an FFR >/=0.96 does not reliably predict an optimal stent result. Higher doses of intracoronary adenosine than previously used to measure FFR improve these results.

Abstract

Vascular remodeling implies the concept of compensatory vessel enlargement to preserve luminal dimensions during atheromatous plaque development. However, negative remodeling, i.e. vessel shrinkage in response to plaque accumulation has also been described. So far, the factors influencing positive or negative remodeling are uncertain. We hypothesized that vascular distensibility, a measure of vessel compliance, is related to compensatory enlargement. In 58 patients undergoing intravascular ultrasound interrogation of a de novo lesion prior to coronary intervention, the cross-sectional vessel area (VA), lumen area (LA) and plaque area (PA = VA minus LA) were measured at end diastole and end systole at the lesion site and at the proximal and distal reference segments. Positive remodeling was defined to be present when the VA at the lesion was > 1.05 times larger than that at the proximal reference (group A), negative remodeling when the VA at the lesion was < 0.95 of the reference site (group C) and in-between was considered to be intermediate (group B). Vessel compliance was measured by calculating vascular distensibility. Results showed a similar LA at the lesion site in all groups (4.18+/-2.18 vs. 4.36+/-1.19 vs. 3.74+/-1.81 mm2, NS) while VA and PA were significantly larger in group A (17.19+/-5.08 vs. 14.22+/-3.66 and 12.45+/-4.82 mm2, p = 0.005 and 13+/-4.55 vs. 9.95+/-3.58 and 8.7+/-3.83, p = 0.003, respectively). Vascular distensibility at the proximal reference segment was significantly greater in group A (3.55+/-2.67 vs. 1.25+/-1.03 and 0.85+/-0.73 mmHg(-1), p < 0.001) with a positive correlation between remodeling and distensibility (R = 0.52, p < 0.001). In a multiple regression model including clinical and lesional factors, distensibility was the only predictor of remodeling. In conclusion, these results suggest that compensatory vessel enlargement occurs to a greater degree in patients with increased coronary artery distensibility, which appears to be a predictor for positive remodeling.

Abstract

The aim of this study was to use serial intravascular ultrasound (IVUS) to evaluate the long-term effect of stent-based 7-hexanoyltaxol (QP2, a taxane analogue) delivery on neointimal tissue growth within the stent and on vessel dimensions at the adjacent reference segments.Serial IVUS analyses (immediately after intervention and at follow-up at 8.3 months) were performed in 15 native coronary lesions treated with the QuaDS-QP2 stent. IVUS measurements were performed at 8 cross-sections in each target segment (4 cross-sections within the stent and 2 cross-sections in each reference segment). At baseline, no significant plaque protrusion or thrombus was detected in the target segment. Mild incomplete stent apposition and edge dissection were observed in one and two cases, respectively. Percent expansion of the stent (minimum stent area/average reference lumen area) was 96.0+/-21.7%. At follow-up, mean neointimal area within the stent was 1.2+/-1.3 mm(2), and mean cross-sectional narrowing (neointimal area/stent area) was 13.6+/-14.9%. At the vessel segments immediately adjacent to the stent, a significant increase in plaque area (1.9+/-2.6 mm(2), P=0.001) was observed, but vessel area remained unchanged. However, no patients showed clinically significant in-stent or edge restenosis (diameter stenosis >/=50%) during the follow-up period.The first human experience with the new drug-delivery stent showed a minimal amount of neointimal proliferation in the stented segment. Late lumen loss at the reference sites adjacent to the stent was acceptable and predominantly due to plaque proliferation.

Abstract

Vessel remodeling is an important mechanism of late lumen loss after nonstent coronary interventions. However, its impact on in-stent restenosis has not been systematically investigated.Serial volumetric intravascular ultrasound analyses (poststent and follow-up) were performed in 55 lesions treated with a balloon-expandable stent (ACS MultiLink) using standard stent deployment techniques. The vessel volume (VV), lumen volume (LV), and volume bordered by the stent (SV) were measured using Simpson's method. The volume of plaque and neointima outside the stent (peri-stent volume, PSV) and volume of neointima within the stent (intrastent volume) were also measured. The change of each parameter during the follow-up period (follow-up minus poststent) was calculated and then divided by SV to normalize these values (designated as percent change [%]). As expected, %PSV directly correlated with %VV (P<0.0001, r=0.935), with no significant SV. A highly significant inverse correlation was seen between %PSV and the percent change of intrastent volume (P<0.0001, r=0.517). Consequently, %LV significantly correlated with peri-stent remodeling, as measured by %VV (P<0.0001, r=0.602).Positive remodeling of the vessel exterior to a coronary stent occurs to a variable degree after stent implantation. There is a distinct trade-off between positive remodeling and in-stent hyperplasia: in segments in which the degree of peri-stent remodeling is less, intrastent neointimal proliferation is greater and accompanied by more significant late lumen loss.

Abstract

Intimal hyperplasia and subsequent in-stent restenosis remain a major limitation after stent implantation. In vitro cell culture studies show that low-frequency, noncavitational ultrasound energy may impact smooth muscle cell proliferation. Accordingly, we assessed the efficacy of intravascular sonotherapy treatment on intimal hyperplasia in a swine stent model.After balloon injury, biliary stents (Johnson & Johnson) were implanted in the femoral arteries of 14 swine. A total of 48 stented sites were randomized to sonotherapy or sham treatment using a custom-built, 8-French catheter intravascular sonotherapy system (URX, PharmaSonics Inc). After stent deployment, ultrasound energy (700 KHz) was applied to the treatment group for up to 5 minutes. Smooth muscle cell proliferation was assessed using bromodeoxyuridine histology preparation (BrdU) at 7 days in 28 stented sites. At 28 days, the neointimal thickness and the ratio of neointimal/stent area (percent stenosis) was calculated by histomorphometric quantification in 20 stented sites. At 7 days, percent of BrdU staining was significantly reduced in the sonotherapy group compared with the sham group (24.1+/-7.0% versus 31.2+/-3.0%, P<0.05). At 28 days, percent stenosis was significantly less in the sonotherapy group than in the sham group (36+/-24% versus 44+/-27%, P<0.05), and the mean neointimal thickness in the sonotherapy group was less than in the sham group (417+/-461 micrometer versus 643+/-869 micrometer, P=0.06).In this swine peripheral model, intravascular sonotherapy seemed to decelerate cellular proliferation and decrease in-stent hyperplasia. Therefore, intravascular sonotherapy may be an effective form of nonionizing energy to reduce in-stent restenosis.

Abstract

We sought to investigate the in vivo mechanical properties of a new self-expanding coronary stent (RADIUS) and, particularly, the subsequent vessel response over time.Preclinical studies have suggested that self-expanding stents may produce less vessel wall injury at initial deployment, leading to larger follow-up lumens than with balloon-expandable stents. However, the influence of the chronic stimulus from self-expanding stents on the vessel wall remains unknown.Sixty-two patients were randomly assigned to either the RADIUS self-expanding stent group (n = 32) or the Palmaz-Schatz balloon-expandable stent group (n = 30). Intravascular ultrasound was performed after stent deployment and at six-month follow-up.At follow-up, the RADIUS stents had increased 23.6% in overall volume, while the Palmaz-Schatz stents had remained unchanged. Due to the greater mean neointimal area (3.0 +/- 1.7 mm2 vs. 1.9 +/- 1.2 mm2, p = 0.02) in the RADIUS group, no significant difference in net late lumen loss was observed between the two groups. On the other hand, analysis at the peristent margins demonstrated that mean late loss was significantly smaller in the RADIUS group than it was in the Palmaz-Schatz group (0.1 +/- 2.1 mm2 vs. 1.9 +/- 2.4 mm2, p = 0.02).Serial volumetric IVUS revealed that the RADIUS stents continued to enlarge during the follow-up period. In this stent implantation protocol, this expansion was accompanied by a greater amount of neointima than the Palmaz-Schatz stents, resulting in similar late lumen loss in both configurations. In the peristent margins, however, late lumen loss was minimized with the RADIUS stents.

Abstract

The study was done to elucidate the relationship between baseline arterial remodeling and clinical outcome following stenting.The impact of preintervention arterial remodeling on subsequent vessel response and clinical outcome has been reported following nonstent coronary interventions. However, in stented segments, the impact of preintervention remodeling on clinical outcome has not been clarified.Preintervention remodeling was assessed in 108 native coronary lesions by using intravascular ultrasound (IVUS). Positive remodeling (PR) was defined as vessel area (VA) at the target lesion greater than that of average reference segments. Intermediate or negative remodeling (IR/NR) was defined as VA at the target lesion less than or equal to that of average reference segment. Remodeling index expressed as a continuous variable was defined as VA at the target lesion site divided by that of average reference segments.Positive remodeling was present in 59 (55%) and IR/NR in 49 (45%) lesions. Although final minimal stent areas were similar (7.76 +/- 1.80 vs. 8.09 +/- 1.90 mm2, p = 0.36), target vessel revascularization (TVR) rate at nine-month follow-up was significantly higher in the PR group (22.0% vs. 4.1%, p = 0.01). By multivariate logistic regression analysis, higher remodeling index was the only independent predictor of TVR (p = 0.02).Lesions with PR before intervention appear to have a worse clinical outcome following IVUS-guided stenting. Intravascular ultrasound imaging before stenting may be helpful to stratify lesions at high risk for accelerated intimal proliferation.

Abstract

Motexafin lutetium (Lu-Tex, Antrin Injection) is a photosensitizer that selectively accumulates in atheromatous plaque where it can be activated by far-red light. The localization and retention of intra-arterially administered Lu-Tex and its efficacy following activation by endovascularly delivered light (photoangioplasty) was evaluated.Bilateral iliac artery lesions were induced in 17 rabbits by balloon denudation, followed by a high cholesterol diet. Lu-Tex distribution within the atheroma was examined (n=8) following local injection. Fluorescence spectral imaging and chemical extraction techniques were used to measure Lu-Tex levels within the atheroma and adjacent normal tissue. Photoactivation was performed 15 min following Lu-Tex administration (180 J/cm fiber at 200 mW/cm fiber). Two weeks post photoangioplasty, vessels were harvested and hematoxylin and eosin (H&E) and RAM11 (macrophages) staining was performed.Local delivery of Lu-Tex achieved immediate high concentrations within plaque (mean 40x control iliac atheroma). Mean percent plaque area in the treated segments was significantly lower than in the non-treated contralateral lesions (73 vs. 82%, P<0.01). No medial damage was observed. Quantitative analysis using RAM11 positive cells revealed significant reduction of macrophages in treated lesions in both the intima (5 vs. 22%, P<0.01) and in media (8 vs. 23%, P<0.01) compared to untreated contralateral segments.Local delivery provides high levels of Lu-Tex selectively within atheroma. Photoactivation results in a significant decrease in macrophage and a small decrease in atheroma burden without damage to the normal vessel wall.

Abstract

Intravascular ultrasound (IVUS) is a valuable adjunct to angiography, providing new insights in the diagnosis of and therapy for coronary disease. Angiography depicts only a 2D silhouette of the lumen, whereas IVUS allows tomographic assessment of lumen area, plaque size, distribution, and composition. The safety of IVUS is well documented, and the assessment of luminal dimensions represents an important application of this modality. Comparative studies show the greatest disparities between angiography and ultrasound after mechanical interventions. In young subjects, normal intimal thickness is typically approximately 0.15 mm. With IVUS, lipid-laden lesions appear hypoechoic, fibromuscular lesions generate low-intensity echoes, and fibrous or calcified tissues are echogenic. Calcium obscures the underlying wall (acoustic shadowing). The extent and severity of disease by angiography and ultrasound are frequently discrepant. Arterial remodeling refers to changes in vascular dimensions during the development of atherosclerosis. At diseased sites, the external elastic membrane may actually shrink in size, contributing to luminal stenosis. The interpretation of IVUS relies on simple visual inspection of acoustic reflections to determine plaque composition. However, different tissue components may look quite similar, and artifacts may adversely affect ultrasound images. IVUS commonly detects occult disease in angiographically "normal" sites. In ambiguous lesions, ultrasound permits lesion quantification, particularly for left main coronary disease. IVUS has emerged as the optimal method for the detection of transplant vasculopathy. An important potential application of ultrasound is the identification of atheromas at risk of rupture. The mechanisms of action of interventional devices have been elucidated using IVUS, and ultrasound is used by some operators to select the most suitable interventional device. IVUS-derived residual plaque burden is the most useful predictor of clinical outcome. In restenosis after balloon angioplasty, negative remodeling is a major mechanism of late lumen loss. IVUS is not routinely used for stent optimization, and there is no consensus regarding optimal procedural end points. Ultrasound has proven useful in evaluating brachytherapy. New and emerging applications for IVUS are continuing to evolve, particularly in atherosclerosis regression-progression trials.

Abstract

The goal of the present study was to compare the use of pressure-derived myocardial fractional flow reserve for detecting ischemia with nuclear stress imaging in patients undergoing stent placement for intermediate coronary lesions. We demonstrated that myocardial fractional flow reserve detects ischemia in intermediate coronary lesions accurately when compared with nuclear stress imaging.

Abstract

Ultra-high-frequency (40- to 50-MHz) intravascular ultrasound (IVUS) improves image quality compared with conventional 20- to 30-MHz IVUS. However, as the frequency of IVUS increases, high-intensity backscatter from blood components may cause visual difficulties in discrimination between the lumen and arterial wall structure. The purpose of this study was to evaluate the effect of a novel blood noise reduction algorithm (BNR) on quantitative coronary ultrasound measurements.IVUS studies using a 40-MHz transducer were performed in 35 patients with coronary artery disease. A total of 620 gray-scale images (310 pairs) were processed with and without the BNR, and lumen cross-sectional area (CSA) was determined by 2 independent observers. With the BNR, the intraobserver and interobserver correlation coefficients for lumen CSA were significantly improved (0.85 to 0.99 and 0.80 to 0.98, respectively). In the 270 images (135 pairs) in which vessel wall measurements were possible, the BNR significantly improved the intraobserver and interobserver correlation coefficients for plaque plus media CSA (0.83 to 0.99 and 0.76 to 0.97, respectively), whereas no influence was observed for external elastic membrane CSA (1.00 to 1.00 and 0.99 to 0.99, respectively).This study demonstrates the feasibility of this novel algorithm to reduce blood noise, thereby enabling accurate lumen border delineation and providing reproducible measurements of both the lumen and plaque plus media CSAs. Incorporating a digital BNR may serve as an important adjunct to ultra-high-frequency IVUS imaging for improving accurate quantitative evaluation of vessel dimensions.

Abstract

Conventional gray-scale images of intravascular ultrasound (IVUS) cannot accurately differentiate histologic subtypes of sonolucent coronary plaques with or without a lipid core.We analyzed radiofrequency signals obtained in vitro from 24 regions of interest (ROI) of noncalcified (sonolucent) plaques in 10 atherosclerotic coronary artery specimens pressure-fixed by formalin. Radiofrequency signals were sampled with a 30-MHz IVUS catheter and digitized at 500 MHz in 8-bit resolution. The ROIs were histologically categorized into 12 plaques with a lipid core and 12 plaques without it. Integrated backscatter and statistical parameters of the radiofrequency envelope (mean/SD ratio [MSR], skewness, and kurtosis) within the ROI were calculated offline, and their ability to detect a lipid core was compared with visual analysis of the IVUS video images. In the group with lipid cores, percent area of a lipid core in each ROI was measured in a digitized histologic image by a computerized planimeter.Sensitivity and specificity of MSR, skewness, and kurtosis for lipid core detection were substantially greater than visual video image analysis (83.3% and 91.7%, 100% and 91.7%, 100% and 91.7% vs 53.3% and 71.7%). Furthermore, the parameters of integrated backscatter, MSR, skewness, and kurtosis were significantly correlated to percent of core area (r = -0.64, -0.73, 0.78, and 0.63, respectively; P

Abstract

Fractional flow reserve (FFR) is a measure of coronary stenosis severity that is based on pressure measurements obtained at maximal hyperemia. The most widely used pharmacologic stimulus for maximal coronary hyperemia is adenosine, administered either as a continuous intravenous (IV) infusion or intracoronary (IC) bolus. IV adenosine has more side effects and is more costly than IC adenosine but has a more stable and prolonged hyperemic effect.We compared the efficacy of IC and IV adenosine administration for the measurement of FFR in a multicenter trial. Fifty-two patients with 60 lesions underwent determination of FFR with both IV and IC adenosine. IV adenosine was administered as a continuous infusion at a rate of 140 microgram/kg per minute until a steady state hyperemia was achieved. IC adenosine boluses were administered at a dose of 15 to 20 microgram in the right and 18 to 24 microgram in the left coronary artery. FFR was calculated as the ratio of the distal coronary pressure (from pressure guide wire) to the aortic pressure (guide catheter) at maximal hyperemia.A total of 26 left anterior descending, 23 right, 9 left circumflex, and 3 left main coronary arteries were evaluated. Mean percent stenosis for both groups was 55.8% +/- 23.6% (range 0% to 95%), and mean FFR was 0.78 +/- 0.15 (range 0.41 to 0.98). There was a strong and linear correlation between FFR measurements with IV and IC adenosine (R = 0.978, y = 0. 032 + 0.964x, P

Abstract

Current immunosuppressive protocols fail to prevent chronic rejection often manifested as graft vascular disease (GVD) in solid organ transplant recipients. Several new immunosuppressants including sirolimus, a dual function growth factor antagonist, have been discovered, but studies of drug efficacy have been hampered by the lack of a model of GVD in primates, as a prelude to clinical trials. As described earlier, we have developed a novel non-human primate model of GVD where progression of GVD is quantified by intravascular ultrasound (IVUS).Twelve cynomolgus monkeys underwent aortic transplantation from blood group compatible but mixed lymphocyte reaction-mismatched donors. To allow the development of GVD in the allograft, no treatment was administered for the first 6 weeks. Six monkeys were treated orally with sirolimus from day 45 after transplantation to day 105.Progression of GVD measured as change in intimal area from day 42 to 105 was halted in sirolimus-treated monkeys compared to untreated monkeys (P<0.001, general linear model). On day 105, the intimal area +/- SEM was 3.7+/-1.0 and 6.4+/-0.5 mm2, respectively (P<0.05, t test). The magnitude of allograft intimal area on day 105 correlated inversely with sirolimus trough levels (R2=0.67, P<0.05). Regression of the intimal area was seen in four of six sirolimus-treated monkeys, which was significantly different from the untreated monkeys (P<0.05).Our results in the first non-human primate model of GVD showed that treatment with sirolimus not only halted the progression of preexisting GVD but also was associated with partial regression. Sirolimus trough blood levels were correlated with efficacy. Therefore, sirolimus has the potential to control clinical chronic allograft rejection.

Abstract

It has been postulated that atherosclerotic plaque deposition is spatially related to regions of low shear in non-branching vessel segments. Intravascular ultrasound (IVUS) allows precise spatial orientation of coronary artery plaque formation in humans. The objective of this study was to test the hypothesis that coronary plaques have a higher prevalence on the myocardial side in regions that encounter low surface shear stress. IVUS allows the determination of the inner versus the outer curve of the vessel based on vascular and perivascular landmarks. We studied 30 consecutive patients pre-intervention using IVUS and measured vessel area, lumen area and plaque area (vessel-lumen area) during a motorized pullback at 1 mm intervals. Vessel segments near a side branch (within two times the diameter of the vessel) were excluded from analysis because of flow disturbances. All plaques were classified as concentric or eccentric and all eccentric plaques were further divided with respect to their spatial orientation in the vessel into quadrants: myocardial (inner curve, lower shear stress), epicardial (outer curve, higher shear stress) and lateral (two quadrants intermediate). A total of 613 cross-sections were analyzed in 14 left anterior descending, six left circumflex, and ten right coronary arteries. Plaque distribution was found to be concentric in 321 (52.4%) and eccentric in 292 (47.6%) cross sections. Of all eccentric plaques, 184 cross sections were oriented toward the myocardial side (62.6%) compared to only 54 toward the epicardial side (17.3%) and 54 in the 2 lateral quadrants (19.5%, P<0.001). No difference in plaque area (6.75+/-2.70 vs. 6.76+/-2.60 mm(2)), vessel area (15.28+/-4.73 vs. 15.35+/-4.40 mm(2)), or plaque thickness (1.26+/-0.37 vs. 1.25+/-0.43 mm) was noted between myocardial or epicardial plaques. These results suggest that atherosclerotic plaques develop more frequently on the myocardial side of the vessel wall, which may relate to lower shear stress. However, plaque size is similar on the epicardial and myocardial side.

Abstract

To test the hypothesis that patients with unstable coronary syndromes show accentuated compensatory vessel enlargement compared with patients with stable angina, and that this may in part be related to increased coronary artery distensibility.In 23 patients with unstable coronary syndromes (10 with non-Q wave myocardial infarction and 13 with unstable angina), the culprit lesion was investigated by intravascular ultrasound before intervention. The vessel cross sectional area (VA), lumen area (LA), and plaque area (VA minus LA) were measured at end diastole and end systole at the lesion site and at the proximal and distal reference segments. Similar measurements were made in 23 patients with stable angina admitted during the same period and matched for age, sex, and target vessel. Calculations were made of remodelling index (VA at lesion site / VA at reference site), distensibility index ([(delta A/A)/delta P] x 10(3), where delta A is the luminal area change in systole and diastole and delta P the difference in systolic and diastolic blood pressure measured at the tip of the guiding catheter during a cardiac cycle), and stiffness index beta ([ln(P(sys)/P(dias))]/(delta D/D), where P(sys) is systolic pressure, P(dias) is diastolic pressure, and delta D is the difference between systolic and diastolic lumen diameters). Positive remodelling was defined as when the VA at the lesion was > 1.05 times larger than at the proximal reference site, and negative remodelling when the VA at the lesion was < 0.95 of the reference site.Mean (SD) LA at the lesion site was similar in both groups (4.03 (1.8) v 4.01 (1. 93) mm(2)), while plaque area was larger in the unstable group (13. 29 (4.04) v 8.34 (3.6) mm(2), p < 0.001). Remodelling index was greater in the unstable group (1.14 (0.18) v 0.83 (0.15), p < 0.001). Positive remodelling was observed in 15 patients in the unstable group (65%) but in only two (9%) in the stable group (p < 0.001). Negative remodelling occurred only in two patients with unstable symptoms (9%) but in 17 (74%) with stable symptoms. At the proximal reference segment, the difference in LA between systole and diastole was 0.99 (0.66) mm(2) in the unstable group and 0.39 (0.3) mm(2) in the stable group (p < 0.001), and the calculated coronary artery distensibility was 3.09 (2.69) and 0.94 (0.83) per mm Hg in unstable and stable patients, respectively (p < 0.001). The stiffness index beta was lower in patients with unstable angina (1.95 (0.94) v 3.1 (0.96), p < 0.001).Compensatory vessel enlargement occurs to a greater degree in patients with unstable than with stable coronary syndromes, and is associated with increased coronary artery distensibility.

Abstract

Graft vascular disease (GVD) is an incompletely understood process and the primary cause of late allograft failure. A nonhuman primate model was established to study the progression of GVD by using serial intravascular ultrasound (IVUS).Aortic allografts were transplanted below the inferior mesenteric arteries (IMA) into 6 rhesus monkeys. Removed and re-implanted aortic segments between renal arteries, and the inferior mesenteric arteries served as autografts. IVUS was performed at days 0, 24, 52, 80, and 98 after transplantation. Vessel area (VA) and lumen area (LA) were measured from each cross-section at 0.5 mm intervals. Intimal index (II=100x (VA-LA/VA)) and corresponding vessel volumes were calculated for the whole grafts. Histologic features were assessed from autopsy samples using computerized morphometric method and a score from 0 to 3 for GVD (0=none, 3=severe).In allografts, vessel volume and luminal volume decreased significantly (P<0.05 for both) and the intimal index increased from 12% to 59% by day 98. These parameters remained unchanged in autografts. Histologic analysis of allografts showed concentric intimal hyperplasia and scattered mononuclear cell accumulations, whereas the autografts had only occasional eccentric intimal changes. The GVD-scores were significantly higher in allografts than in autografts (median 3 vs. 1, P=0.042).We introduce a nonhuman primate model of GVD that enables serial IVUS assessments of multiple parameters of GVD. Concentric intimal proliferation and decrease of vessel dimensions was observed in allografts as a consequence of alloimmunity. This is a potential new model for studying new therapies to prevent GVD or halt its progression.

Abstract

Intravascular ultrasound (IVUS) can assess stent geometry more accurately than angiography. Several studies have demonstrated that the degree of stent expansion as measured by IVUS directly correlated to clinical outcome. However, it is unclear if routine ultrasound guidance of stent implantation improves clinical outcome as compared with angiographic guidance alone.The CRUISE (Can Routine Ultrasound Influence Stent Expansion) study, a multicenter study IVUS substudy of the Stent Anti-thrombotic Regimen Study, was designed to assess the impact of IVUS on stent deployment in the high-pressure era. Nine centers were prospectively assigned to stent deployment with the use of ultrasound guidance and 7 centers to angiographic guidance alone with documentary (blinded) IVUS at the conclusion of the procedure. A total of 525 patients were enrolled with completed quantitative coronary angiography, quantitative coronary ultrasound, and clinical events adjudicated at 9 months for 499 patients. The IVUS-guided group had a larger minimal lumen diameter (2.9+/-0.4 versus 2.7+/-0. 5 mm, P<0.001) by quantitative coronary angiography and a larger minimal stent area (7.78+/-1.72 versus 7.06+/-2.13 mm(2), P<0.001) by quantitative coronary ultrasound. Target vessel revascularization, defined as clinically driven repeat interventional or surgical therapy of the index vessel at 9 month-follow-up, occurred significantly less frequently in the IVUS-guided group (8.5% versus 15.3%, P<0.05; relative reduction of 44%).These data suggest that ultrasound guidance of stent implantation may result in more effective stent expansion compared with angiographic guidance alone.

Abstract

Automated edge detection may standardize measurements among observers, providing for rapid assessment of intravascular ultrasound (IVUS) images. However, with high frequency images, enhanced blood signals make it difficult to define and trace the lumen borders. Accordingly, we evaluated a fully automated contour analysis facilitated with a blood noise reduction algorithm (BNR) for 40-MHz IVUS images in human coronary arteries of 27 patients. This algorithm is based on the principle that blood echo speckles have higher temporal and spatial variations than the arterial wall. A total of 193 paired lumen areas and 78 external elastic membrane (EEM) areas were measured and compared. Automated measurements showed good agreement with manual tracings for lumen and EEM area, with high correlation coefficients (0.945 and 0.950, respectively) and small variability (0.4 +/- 14.4% and 0.6 +/- 9.7%, respectively). This preliminary finding suggests that automated contour detection facilitated with BNR appeared to be a feasible and reliable technique for area measurements in 40-MHz IVUS imaging.

Abstract

The poor long-term outcome in young diabetic patients receiving stents is not well understood. The purpose of this study was to characterize the pastprocedural results of stent placement in diabetic patients using intravascular ultrasound to identify factors that might be associated with poor clinical outcome. The acute dimensions from intravascular ultrasound studies after stent deployment at 5 sites were measured from 39 coronary segments from patients with diabetes mellitus (DM) and 161 segments from nondiabetic patients (non-DM). Within these 2 groups, segments were subgrouped into young (y) and old (o) in reference to the mean study age of 64 years, forming 4 groups: yDM (n = 20), y non-DM (n = 65), oDM (n = 19), and o non-DM (n = 96). Results are reported as mean +/- 1 SD. Diabetic patients had smaller mean lumen area within the treated segment than o non-DM (8.37+/-2.59 vs. 9.11+/-3.35 mm2, p<0.01). These differences were more pronounced at the distal reference vessel lumen of yDM than y non-DM (7.6+/-2.3 vs. 10.3+/-4.5 mm2, p<0.003), and were associated with greater percent plaque area in the distal reference vessel (43.4+/-13% vs. 34.1+/-11.2%, p<0.003). In young diabetic patients undergoing elective stent placement, underexpansion of the stented segment is common, which may contribute to the relatively poor long-term outcome in these patients. We suggest that when stenting is the procedure of choice in this subgroup of high-risk patients, special attention should be given to optimizing lumen dimensions.

Abstract

Measurements of Doppler derived coronary flow reserve (CFR) and pressure derived fractional flow reserve (FFR) for coronary stenosis assessment depend on the induction of maximal hyperemia. Adenosine is the most widely used pharmacological agent but is expensive and poorly tolerated by some patients.The objective of this study was to test the equivalency of adenosine 5'-triphosphate (ATP) to adenosine in their ability to cause maximal hyperemia as compared with the hyperemic response of complete coronary occlusion in 6 canines. Intracoronary administration of either ATP or adenosine resulted in a significant increase in CFR (2.79+/-0.64 and 2.22+/-0.7 for 10 microgram versus 4. 65+/-1.22 and 4.25+/-0.78 for 100 microgram for ATP and adenosine, respectively, P for trend <0.001) but not reaching the level of coronary occlusion (6.35+/-2.26). Additionally, FFR and CFR were measured in 35 different stenoses using ATP, adenosine, and coronary occlusion. There was an excellent linear correlation between ATP and adenosine for both CFR (R=0.934, P<0.001) and FFR (R=0.985, P<0.001). However, hyperemia with either ATP or adenosine was less than postocclusion hyperemia, resulting in significantly different reserve measurements (CFR: 1.93+/-0.66 and 2.08+/-0.81 versus 2.35+/-0.97, P<0.001; FFR: 0.62+/-0.24 and 0.63+/-0.23 versus 0.58+/-0.2, P<0.001).1) Step up in dosage of ATP and adenosine beyond currently recommended clinical doses resulted in a significant increase in coronary hyperemia; 2) ATP was equivalent to adenosine for both CFR and FFR; and 3) complete coronary occlusion yielded a better hyperemic response than either drug, indicating that maximal hyperemia was not achieved by either pharmacological stimulus.

Abstract

We investigated the efficacies of sirolimus (rapamycin) and cyclosporine for inhibition of graft vascular disease (GVD) in cynomolgus monkey recipients of aortic allografts. Increases in arterial intimal thickening in the midgraft (six consecutive cross-sections) after transplantation were quantified by serial intravascular ultrasound (IVUS) from day 21 to day 105. These data enabled correlations between changes in intimal indexes [II = (intimal area/vessel area) x 100] and trough levels of sirolimus and cyclosporine to be determined. Eighteen recipients received no immunosuppression for 6 weeks to allow alloimmune injury to occur. On day 45, monkeys were treated daily with sirolimus (n = 6) or cyclosporine (n = 6); six monkeys remained untreated. II increased significantly from day 63 to day 105 in untreated monkeys and monkeys treated with cyclosporine, whereas monkeys treated with sirolimus did not have a significant increase in II (P = 0.008, P = 0.006, P = NS; paired t-test). The change in II from days 63 to 105 was significantly greater in untreated monkeys compared to sirolimus-treated monkeys (P = 0.13; one-way ANOVA, P = 0.012 Tukey's post hoc test); other post hoc pairwise comparisons were not significant. Mean sirolimus and cyclosporine levels +/- SEM were 43 +/- 7 ng/ml and 562 +/- 20 ng/ml, respectively. Sirolimus trough levels, but not cyclosporine levels, correlated inversely with changes in II from day 42 to 105 (r2 = 0.73, P = 0.03). This non-human primate study shows that inhibition of intimal thickening by sirolimus depends on trough levels and provides the rationale for clinical trials of sirolimus for the control of GVD in organ transplant recipients.

Abstract

Guidewire-based coronary pressure measurement has emerged over the last years as a promising approach in the invasive assessment of coronary artery disease. It enables calculation of fractional flow reserve (FFR) which closely relates distal coronary pressure to myocardial blood flow during maximal arteriolar vasodilation. Coronary pressure measurement and FFR provide important information, both for decision making in diagnostic angiography and for monitoring and evaluating coronary interventions. In this review, the practical set-up of coronary pressure measurement in the catheterization laboratory is discussed step-by-step, special attention is given to potential pitfalls and how to avoid them, and the interpretation of coronary pressure measurement in a variety of pathologic conditions is clarified. Cathet. Cardiovasc. Intervent. 49:1-16, 2000.

Abstract

Unprocessed ultrasound radiofrequency (RF) signal analysis has been shown to distinguish different tissue structures more reliably than gray-scale interpretation of conventional ultrasound images.The objective of this study was to test the feasibility of in vivo intravascular ultrasound (IVUS) RF signal analysis in an animal model of allograft rejection. Six cynomolgus monkeys underwent transplantation of 3-cm aortic allograft segments distal to the renal arteries from immunologically mismatched donors. IVUS imaging with a 30-MHz system was performed 84 to 105 days after the operation. RF signals were acquired from cross sections of the recipient and the allograft aortas in real time with a digitizer at 500 MHz with 8-bit resolution. Sixty-five cross sections and 68 regions of interest (31 in host aorta and 37 in allograft) were analyzed in the adventitial layer with a total number of 8568 vectors processed. For each region of interest, a weighted-average attenuation was calculated on the basis of the attenuation and length for each individual vector. Histological examination was performed at every cross section imaged by IVUS. When the gray-scale images of conventional IVUS scored by an independent observer were compared, no distinction between adventitia of the native aorta and allograft was possible. Analysis of the average RF backscatter power also showed no significant difference (70.32+/-3.55 versus 70.72+/-3.38 dB). However, the average attenuation of allografts was significantly lower than that of the host aortas (2.64+/-1.38 versus 4.02+/-1.16 dB/mm, P<0.001). Histology demonstrated a marked adventitial inflammatory response in all allografts, with no inflammation observed in the host aortas.In vivo IVUS tissue characterization can be performed during routine imaging. In this model of transplant vasculopathy, RF attenuation measurements were more sensitive than visual or quantitative gray-scale analysis.

Abstract

We tested the ability of ultrasound radiofrequency (RF) signal analysis to characterize thrombus accumulation in a Dacron graft incorporated into the exteriorized arteriovenous shunt in 3 baboons with constant blood flow for 60 min. Thrombus formation was quantified by sequential measurements of 111Indium-labeled platelet deposition. RF signals were acquired every 15 min at 2 sites in the graft, using a 2.9 Fr intravascular ultrasound catheter-based transducer (30 MHz) and digitized at 250 MHz in 8-bit resolution. Regions of interest were placed within a 0.5-mm perimeter adjacent to the graft wall. Integrated backscatter increased significantly (p < 0.001) with increasing platelet deposition. However, mean-to-standard deviation ratio of the RF envelope showed no significant change and the distribution pattern of the RF probability function remained constant and consistent with a Rayleigh scattering process. These results provide a basis for using RF analysis to monitor the time-course of thrombus formation.

Abstract

Palmaz-Schatz stents were implanted in 79 lesions in 76 patients, and serially expanded at 12, 15, and 18 atm of pressure using noncompliant balloons. By core lab analysis, intravascular ultrasound demonstrated marked stent expansion as pressure was raised, which was not apparent by angiography.

Abstract

In this study, we summarize the role of residual plaque burden, as determined by intravascular ultrasound, on the development of restenosis following percutaneus coronary interventions. Several clinical trials have shown that the amount of residual plaque is a consistent and independent predictor of subsequent restenosis. The impact of residual plaque burden on late lumen loss is particularly augmented by negative vessel remodeling that is commonly seen after balloon angioplasty and atherectomy. However, early evidence suggests that the importance of plaque burden also applies in the context of stenting. The cotreatment of debulking may further improve the long-term outcome of stenting by maximizing an acute lumen gain with less vessel stretching, preventing stent edge problems and possibly reducing the cell source involved in the intimal hyperplastic process. Evaluation of residual plaque burden with on-line intravascular ultrasound could lead to definitive therapies via risk stratification of the treated segments.

Abstract

The validity of quantitative coronary angiography (QCA) after stent placement has been questioned because the optical density of a metallic stent, added to the density of a contrast-filled lumen, could affect border definition. METHODS andWe deployed 3.0- and 4.0-mm Palmaz-Schatz, Wiktor, Multilink, NIR, and InStent stents in precision-cast phantoms. Central lumens of 2.0 mm were created. There was no difference between the "true" diameters of any stented lumen by both QCA and quantitative ultrasonic (QCU) measurement poststenting. QCA systematic error (SE) varied from 0.01 for the Wiktor stents to 0.14 mm for the Palmaz-Schatz stents; the random error (RE) was 0.03 to 0.14 mm. QCU SE varied from 0.05 to 0.11 mm, and RE ranged from 0.01 to 0.07 mm. At the next stage, 4.0-mm Wiktor and Palmaz-Schatz stents were deployed into the phantom lumens; 1.5-, 2.0-, 2.5- and 3.0-mm lumens were created inside the stents. QCA and QCU measurements of 1.5- to 2.5-mm residual lumens were overestimated by 0.1 to 0.3 mm. In the 3. 0-mm residual lumen within the Wiktor stent, QCA underestimated the luminal size by -0.1 mm. There was no QCA inaccuracy for a 3.0-mm lumen within the Palmaz-Schatz stent. In patients, in 25 stented segments in both the Palmaz-Schatz and Wiktor groups, there was no difference between QCA and QCU diameters.QCU is sufficiently precise for the assessment of the coronary lumen after stenting. QCA can be used as an accurate method of poststent assessment, except when a very mild recurrence within a highly opaque stent is measured. In that instance, QCA may underestimate the luminal diameter.

Abstract

In January 1997, experts from the United States, Europe, and Japan gathered at Stanford University to review their collective experience with intracoronary and noncoronary stenting and to identify and prioritize issues requiring further clinical investigation. This report summarizes the discussions that took place during this stent summit. Knowledge of stent-tissue interaction from animal and human pathologic specimens was reviewed in the context of evolving stent designs. The relative merits of coil and slotted tubular stent designs were discussed. Stent deployment routines, including self-expansion, balloon expansion, and high-pressure delivery were debated. The potential for covered stents and coated stents was explored. Problems surrounding the routine deployment of stents were identified: small vessel disease, long lesions, bifurcation stenoses, vein graft disease, ostial disease, left main stenoses, and intrastent restenosis. The value of intravascular ultrasound, as an adjunct to stenting, was explored and debated. An algorithm for "provisional stenting" based on ultrasound criteria was developed. Noncoronary stenting of the aorta, iliacs, and carotids were discussed. Clinical applications that may lead to randomized clinical trials were identified.

Abstract

Intravascular ultrasound (IVUS) images are typically viewed and recorded in an arbitrary rotational orientation. This study was performed to validate a new method for improved orientation of sonographic vascular cross-sections.We have tested a simple technique for rotational indexing of IVUS in cases in which guiding catheters with side holes are used. Although guiding catheters are opaque to ultrasonography, the side holes transmit the beam and therefore can be easily identified. The orientation of the side holes, which is characteristic for each make of guiding catheter, can be used to determine the anatomically appropriate rotational orientation of the IVUS image. In this study images of four commercially available side-hole guiding catheters were viewed in vitro to confirm the visibility of the side holes and to characterize their orientation for purposes of rotational orientation of images. Feasibility tests of rotational orientation based on side holes were then performed in canine coronary arteries (n = 3) and in six human coronary arteries. Three serial imaging runs in each clinical case yielded a mean variability in rotational orientation of 7.5 +/- 1.5 degrees.Validation testing of the side-hole technique demonstrates the potential for consistent and anatomically appropriate orientation of intravascular ultrasound images.

Abstract

A variety of new devices in the field of intravascular ultrasound imaging are being designed and tested. Mechanical intravascular ultrasound (IVUS) devices with rotating transducers have been developed that allow transducer pullback with integrated longitudinal 2-dimensional displays. Recent advances in the area of imaging include (1) solid-state systems that combine ultrasound with balloon and stent placement; (2) combined imaging atherectomy devices; (3) imaging cores or guidewires; (4) forward-looking devices; (5) 3-dimensional reconstruction techniques; (6) high-frequency imaging; and (7) improved methods for characterizing tissue. Other promising approaches include magnetic resonance imaging, thermography, and optical coherence tomography. An important goal for long-term technologic improvement is visualization of lipid accumulations and fibrous caps during their early stages of development.

Abstract

Previous clinical trials of directional coronary atherectomy (DCA) have failed to show significant improvement in early or late outcomes compared with balloon angioplasty (PTCA). The present study tested the hypothesis that more aggressive "optimal" atherectomy could be performed safely to produce larger initial lumen diameters and a lower late restenosis rate.The present study was a prospective multicenter registry of consecutive patients undergoing optimal DCA of de novo or restenotic lesions in 3.0- to 4.5-mm native coronary arteries. Optimal DCA was defined as using a 7F atherectomy device and adjunctive PTCA if necessary to achieve a < 15% residual stenosis. Six-month angiographic and 1-year clinical follow-up was planned in all patients. A total of 199 patients with 213 lesions met eligibility criteria for enrollment. Short-term procedural success was achieved in 97.5%, with a major complication rate (death, emergency bypass surgery, or Q-wave myocardial infarction [MI]) of 2.5%. There were no early deaths. Non-Q-wave MI (CK-MB > 3 times normal) occurred in 14% of patients. Mean reference vessel diameter was 3.28 mm. Mean diameter stenosis was reduced from 63.5% to a final stenosis of 7%. Late 1-year clinical follow-up revealed one cardiac death and a target lesion revascularization rate of 17.8%. The angiographic restenosis rate at 6 months was 28.9%, with the major predictor of restenosis being a smaller postprocedure lumen diameter.Optimal DCA produced a low residual percent diameter stenosis and a lower restenosis rate than seen in previous trials without an increase in early or late major adverse events.

Abstract

Over the past 5 years intravascular ultrasound imaging has achieved many technical advancements both in catheter design and image quality. In addition to improved image quality that provides clear display of the endovascular structure, efficient signal penetration permits the viewing of structures beyond the artery by highlighting the perivascular structures. These perivascular landmarks, which are unique within a particular coronary segment, help provide both axial and spatial orientation during multiple imaging runs throughout a coronary artery. Orientation on the basis of veins and pericardium assists the operator to appreciate the full three-dimensional view of a particular coronary segment. This article describes several of the common perivascular structures that may be viewed from different arteries routinely imaged during coronary procedures.

Abstract

The purpose of this study was to evaluate the safety, feasibility, optimal deployment technique and 1-year clinical outcome for the Advanced Cardiovascular Systems (ACS) MultiLink stent.Optimal stent deployment assessed by quantitative coronary angiography and intravascular ultrasound (IVUS) is associated with improved clinical outcome.Forty-nine consecutive patients with a discrete stenosis in a native coronary artery 3 to 4 mm in diameter were treated with the new, balloon-expandable ACS MultiLink stent. Stent expansion was assessed in all patients using quantitative coronary angiography and serial IVUS imaging after 8-, 12- and 16-atm inflations. Clinical follow-up was obtained at 30 days and 1 year.All 49 patients had successful placement of a MultiLink stent without death, emergency coronary artery bypass graft surgery or Q wave myocardial infarction. After placement of the MultiLink stent, the minimal lumen diameter increased from 1.24 to 2.98 mm (p < 0.001), and diameter stenosis decreased from 61% to 7% (p = 0.001). Minimal lumen cross-sectional area by IVUS increased progressively after 8, 12 and 16 atm (5.6 to 6.8 to 7.4 mm2, respectively, p < 0.001). However, only 64% of stents achieved a lumen/reference area ratio > or = 70%. No adverse clinical events occurred by 30 days, and by 1 year only one patient (2.0%) required revascularization of the stented artery.Treatment of stenoses in native coronary arteries with the MultiLink stent is associated with a high success rate and a low incidence of adverse events by 1 year, despite the fact that the majority of stents did not meet IVUS-defined criteria for "optimal stenting" derived from first-generation devices.

Abstract

The AVE Micro Stent (AVE Inc., Santa Rosa, CA) is composed of helically welded 3 mm long, zigzag crowns with stent lengths from 6 to 39 mm and diameters from 2.5 to 4.5 mm. Quantitative coronary angiography and histologic analyses of acute and chronic implantation were obtained in 52 stented coronary segments of 18 dogs. Three hearts with 8 stented coronary segments were harvested after 24 hr, 3 hearts with 9 stented segments were harvested after 2 weeks, 6 hearts with 15 stented segments were harvested at 8 weeks, and 6 hearts with 20 stented segments were harvested at 24 weeks post-deployment. There were no procedural complications, deaths, or acute vessel closures. The average lumen diameter of the stented segment was largest at 2 weeks (3.3 +/- 0.3 mm). The smallest average diameters were observed at 8 weeks after the stent deployment (2.7 +/- 0.4, P < 0.05) with an increase again at 24 weeks (2.9 +/- 0.6). The pre-explant percent of stenosis was <30% in all animals. Histologically, a peak of inflammation was visible at 2 weeks; however, the extent of luminal narrowing reached its peak at 8 weeks and the lumen dimension increased somewhat at 24 weeks. The degree of intimal thickening remained relatively constant throughout the different time points (<200 microm). Overall, these data suggest that constrictive remodeling within the stented segment occurs at 8 weeks in this animal model. The later increase of the stented segment dimensions as well as higher net gain at 24 weeks compared to 8 weeks after deployment suggests that this constriction is a transitory phenomenon.

Abstract

Intravascular ultrasound has dramatically changed our view of atherosclerotic disease and has helped to define mechanisms of therapeutic interventions, providing a new rationale for selection of appropriate devices. Currently, this technology is used for sizing and orientation of commonly performed interventions such as balloon angioplasty and directional atherectomy. The information from intravascular ultrasound has also led to a dramatic change in the deployment algorithm of stents. Further improvements in catheter design and the findings from clinical trials utilizing intravascular ultrasound will help define a practical role for this new technology.

Abstract

IVUS provides a new gold standard for visualization and measurement of coronary artery disease. Morphologic and morphometric observations by IVUS are in general considerably more detailed and accurate than those obtained by angiography. IVUS has led to new insights into the pathophysiology of coronary plaque accumulation with respect to adaptive vessel responses (remodeling) and their exhaustion (de-remodeling, shrinkage). Further technologic refinements need to focus on issues such as improvement in resolution and miniaturization of IVUS catheters to enhance the applicability of this imaging technique.

Abstract

We sought to determine the effect of inhomogeneous distribution of beam power produced by Doppler catheters on measurements of mean and peak velocity of coronary blood flow.Measurements of mean velocity of coronary blood flow by Doppler catheters have significant systematic errors that have not been completely characterized. We hypothesized that one error is the inhomogeneous distribution of the ultrasonic beam power and that this inhomogeneity makes measurements of mean, but not peak, velocity inaccurate.We constructed a scaled-up model of a Doppler catheter to allow for accurate measurement of the distribution of beam power by miniature hydrophones. This catheter was placed in a model of coronary blood flow in which the fluid velocity was accurately measured by an external laser Doppler velocimeter. The laser Doppler measurements of mean velocity were compared with the measurements of mean velocity made by the catheter, using fast Fourier transform analysis, both without and with correction for inhomogeneous beam power distribution. Peak velocity measurements were also compared, as predicted from theory, without the need of correction for inhomogeneous beam power distribution. To investigate the clinical relevance of our results, we conducted studies using a clinical Doppler catheter both in a scaled model of coronary flow and in a series of eight patients. In the model and in each patient, we rotated the catheter without changing the axial position to systematically alter the relation of the beam power distribution to the local fluid dynamics.The measurement of beam power distribution revealed significant inhomogeneity. Comparison of the measured mean frequency shifts without correction for inhomogeneities in the distribution yielded a statistically significant difference. After correction for inhomogeneities, there was no statistically significant difference. Also, there was no significant difference for the peak frequency shifts. Rotation of the clinical catheter in the scaled model and in the patients changed the measured mean velocity (average change 18.8% and 20.6%, respectively), but not the measured peak velocity (average change 5.0% and 4.3%, respectively).For signal analysis using a fast Fourier transform, the inhomogeneous distribution of power of the ultrasonic beam produced by Doppler catheters makes measurements of mean, but not peak, velocity inaccurate. Measurements of peak velocity may therefore prove superior to measurements of mean velocity in estimating the response to pharmacologic intervention and in estimating stenosis severity.

Abstract

Stent deployment strategies have changed significantly in the past 2 yr, with "high-pressure" balloon inflations postdilatation being performed in the large majority of cases. There is currently little information about the effects of high pressure on the geometry of stent expansion and on the adjacent areas of the vessel wall. Intravascular ultrasound (IVUS) imaging is well-suited to investigate these issues, since it provides information not only about stent expansion and apposition but also about adjacent vessel-wall morphology at transition points such as the articulation site of the stent and the the stent borders. We report on the results of a cohort of 30 consecutive stent cases which were systematically examined by IVUS following high-pressure inflation. All deployments were deemed successful by angiographic inspection. However, in 6 cases, intimal disruptions or "edge tears" were noted at the stent borders by IVUS. In 5 cases, edge tears were seen to occur at the distal border, whereas in one case edge tears were seen at both the proximal and distal edges of the stent. No angiographic and sonographic parameters were different except percent plaque area at the stent margins, which was significantly higher (53 +/- 11%) in the lesions with edge tears, compared to 40 +/- 10% plaque area in the group without evidence of pocket flaps (P = 0.007). This experience suggests that intimal disruptions or "edge tears" are a relatively common occurrence following high-pressure stent deployment, and may be related to the extent of marginal dissections.

Abstract

This study sought to evaluate the extent of atherosclerosis in coronary and iliac arteries in patients with heterozygous familial hypercholesterolemia or familial combined hyperlipidemia, using intravascular ultrasound imaging.Intravascular ultrasound imaging provides cross-sectional tomographic views of the vessel wall and allows quantitative assessment of atherosclerosis.Forty-eight nonsmoking, asymptomatic patients with heterozygous familial hypercholesterolemia or familial combined hyperlipidemia underwent intravascular ultrasound imaging of the left anterior descending coronary, left main coronary and common iliac arteries. Angiography showed only minimal or no narrowing in these vessels. Intravascular ultrasound images obtained during catheter pullback underwent morphometric analysis. Plaque burden was expressed as the mean and maximal intimal index (ratio of plaque area and area within the internal elastic lamina) and as the percent of vessel surface covered by plaque.Intravascular ultrasound detected plaque more frequently than angiography in the left anterior descending (80% vs. 29%, respectively), left main (44% vs. 16%) and iliac arteries (33% vs. 27%). Plaque burden was higher in the left anterior descending (mean intimal index [+/- SD] 0.25 +/- 0.16) than in the left main (0.11 +/- 0.16, p < 0.001) and iliac arteries (0.02 +/- 0.04, p < 0.001). Angiography detected lumen narrowing only in coronary arteries with a maximal intimal index > or = 0.42 (left anterior descending artery) and > or = 0.43 (left main artery). The area within the internal elastic lamina increased with plaque area in the left anterior descending (r = 0.82, p < 0.001) and left main arteries (r = 0.53, p < 0.001). By stepwise multiple regression analysis, the strongest predictor for plaque burden in the left anterior descending artery was the level of high density lipoprotein (HDL) cholesterol and total/HDL cholesterol ratio for the left main artery.In patients with heterozygous familial hypercholesterolemia and familial combined hyperlipidemia, extensive coronary plaque is present despite minimal or no angiographic changes. Compensatory vessel enlargement and diffuse involvement with eccentric plaque may account for the lack of angiographic changes. Levels of HDL cholesterol and total/HDL cholesterol ratio are far more powerful predictors of coronary plaque burden than are low density lipoprotein cholesterol levels in these patients with early, asymptomatic disease.

Abstract

Intravascular ultrasound (IVUS) imaging provides cross-sectional views of the vessel lumen; however, lumen measurements still rely on operator-dependent border delineation and time-consuming lumen tracings. We tested a new system for automated lumen border detection in IVUS images based on acoustic quantification of blood and vessel wall. In 10 rabbits, 29 segments of the aorta were imaged in vivo using a 2.9-Fr IVUS catheter. IVUS images were obtained during motorized pullbacks of aortic segments of 18 mm length. Automated measurements of lumen dimensions were compared to automated measurements of a second pullback through the same segment, lumen measurements derived from visual border tracings in IVUS images, and to quantitative angiography. The automated system showed good reproducibility: Correlations for repeated measurements of lumen area, maximal and minimal lumen diameters were r = 0.97, r = 0.91, and r = 0.93, respectively. Automated measurements also correlated well to visual image analysis (lumen area, r = 0.97; maximal lumen diameter, r = 0.89; minimal lumen diameter, r = 0.89) and to angiographic measurements (lumen area, r = 0.93; lumen diameter, r = 0.95). In 12% of the images, the automated system overestimated lumen dimensions because of weak wall signals in the presence of echolucent structures next to the wall. Signal artifacts from the IVUS catheter itself or strong blood backscatter resulted in lumen underestimation in 6% of the images. Over- and underestimation of lumen by the border detection system were often associated with eccentric catheter position. Thus, lumen measurements in vivo IVUS images can be performed using an automated border detection system based on acoustic quantification of blood and vessel wall. The system allows reproducible and accurate measurements of lumen area and diameters. (ECHOCARDIOGRAPHY, Volume 13, November 1996)

Abstract

Seven hundred ten high speed rotational atherectomy (HSRA) procedures were performed in a single consecutive series of 656 patients. Stand alone HSRA was performed in 253 patients (35%). HSRA with adjunctive low pressure (< or = 2 ATM) balloon angioplasty (LP BA) was performed in 221 patients (31%), and HSRA with adjunctive high pressure (> or = 4 ATM) balloon angioplasty (HP BA) was performed in 236 patients (34%). Prognostically unfavorable Type B2 and C lesions dominated the study group (74.7%). Procedural success rate was 96%. Emergency coronary artery bypass surgery was performed in 1.4% of cases, Q wave myocardial infarction occurred in 3.4% and death, related to procedure, was consequent in 0.5% of cases. Incidence of flow limiting dissections was 3.1%, distal spasm was 5.3%, and "no reflow" phenomenon was 1.8%. The recent technique modifications included continuous advancer/guiding catheter infusion of the nitroglycerin-verapamil mixture, limitation of duration of lesion engagement by the burr, stepwise increase in the burr size, decrease of rotational speed, and strict control of rpm drop during lesion ablation. Evolution of the interventional technique involved trends towards decrease of the use of HP BA in conjunction with steady increase in the percentage of SA and LP BA procedures over time. These technique changes resulted in complete absence of "no reflow" in 1994, as well as a generalized decrease in overall coronary vascular reactivity from all burr passes.

Abstract

The infusion sleeve is a novel drug-delivery catheter system designed to deliver an agent under controlled conditions into the arterial wall at the site of angioplasty. The purpose of the present study was to characterize the delivery agent via the infusion sleeve in ex vivo and in vivo models.The delivery of horseradish peroxidase via the infusion sleeve was studied in a porcine explanted heart model. Under physiological conditions, arteries underwent balloon injury (approximately 10% overstretch), after which horseradish peroxidase (2.5 mL) was delivered at specific pressures. Cross-sectional analysis demonstrated greater staining when the agent was delivered at increasing pressures. The infusion sleeve was evaluated in an in vivo canine coronary model. With an infusion sleeve loaded over a standard dilatation catheter through a 9F guide, overstretch balloon injury was performed, after which fluoresceinated heparin was delivered. Animals were killed 2 hours after delivery. Fluoresceinated heparin-treated segments demonstrated high fluorescence signals, localizing with smooth muscle cell nuclei with less activity in the interstitium. The functional significance of intramural heparin delivery was studied in a porcine carotid model. In the presence of 111In-labeled platelets, arteries underwent overstretch injury followed by delivery of heparin (50 or 100 units/kg) or vehicle. Platelet deposition was reduced at 30 minutes (57%, P < .01) and 12 hours (39%, P = .06) compared with saline controls.Agent delivery via the infusion sleeve is pressure dependent; transmural delivery is possible with minimal disruption of arterial wall architecture; the infusion sleeve is compatible with standard angioplasty equipment; and heparin delivery at the site of balloon injury significantly reduces platelet deposition in a porcine model for a minimum of 12 hours.

Abstract

We sought to examine the immediate vasodilator effect of intracoronary estrogen on epicardial and resistance coronary arteries in 19 dogs.Although estrogen reportedly dilates coronary arteries in vitro, the site and mechanisms of its action have not been fully defined in vivo.Epicardial coronary artery dimensions and coronary flow velocity were assessed using simultaneous intracoronary two-dimensional and Doppler ultrasound.Estrogen (0.1 and 1 mumol/liter) induced a significant increase in coronary cross-sectional area, flow velocity and volumetric blood flow. Estrogen-induced vasodilation was not influenced either by pretreatment with N omega-nitro-L-arginine methyl ester (L-NAME) (100 mumol/liter intracoronary), indomethacin (5 mg/kg body weight intravenously), propranolol (0.75 mg/kg intravenously) or the classic estrogen receptor antagonist ICI 182,780 (10 mumol/liter). Balloon denudation of the endothelium did not attenuate estrogen-induced epicardial vasodilation. Pretreatment with glibenclamide (10 mumol/liter) attenuated estrogen-induced vasodilation only in epicardial arteries, as did verapamil (0.1 mumol/liter). Estrogen had no effect on a phenylephrine dose-response curve in either epicardial coronary arteries or the microcirculation.Acute estrogen-induced dilation in canine coronary arteries is endothelium independent and is not mediated by the classic intracellular estrogen receptor but through non-genomic mechanisms, presumably at the membrane level, which in epicardial arteries may include effects on adenosine triphosphate-sensitive potassium or calcium channels, or both.

Abstract

Reduced epicardial coronary arterial distensibility associated with early atherosclerosis may be mediated in part by reduced nitric oxide (NO) release. To directly assess the contribution of endogenous NO to coronary arterial distensibility, we examined the effect of intracoronary N omega nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase, and L-arginine, its natural substrate, on the circumflex artery in seven anesthetized dogs. We also used intracoronary acetylcholine to examine the effect of pharmacologically induced NO release on coronary distensibility. Electrocardiographically gated measurements of epicardial coronary lumen area were made by a blinded observer from images obtained with a 4.3F, 30 MHz intravascular ultrasound catheter. Aortic root pressure was continuously monitored, and neither systemic arterial pressure nor pulse pressure changed significantly with intracoronary drug administration. Change in lumen area (delta LA) from end systole to end diastole was measured, and an arterial distensibility index was calculated. Delta LA increased with acetylcholine from 8.2% +/- 0.5% at baseline to 16.3% +/- 2.8% (10(-6) mol/L; p < 0.001), with increases in both end-systolic and end-diastolic lumen area and decreased delta LA to 3.1% +/- 1.3% (p < 0.01). Lumen area and delta LA were both restored to baseline by L-arginine (10(-4)). The calculated distensibility index of the epicardial coronary artery was enhanced by acetylcholine, reduced below baseline by L-NAME, and restored to baseline by L-arginine.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract

Directional atherectomy removes plaque in a targeted portion of a vessel wall. In practice, orienting the cutter toward maximal plaque accumulation and assessing the depth of vessel excision is difficult with angiographic guidance alone. Accordingly, we designed and tested a prototype catheter that combines ultrasound imaging capability with directional atherectomy in a single device. Twenty-seven in vitro vessels (32 lesions) were treated with atherectomy alone or with atherectomy combined with ultrasound. Lesion characteristics before and after the procedure were similar in each group. A significant decrease in the incidence of subintimal tissue excision was observed in the atherectomy-ultrasound group (21.1%) compared to the group that had debulking with atherectomy alone (54.5%). In addition, among specimens with media and/or adventitia the relative amount of subintimal tissue was significantly less (p < 0.001) with ultrasound guidance than with atherectomy alone (11.2% +/- 10.1% vs 34.2% +/- 8.5%). We conclude that ultrasound-guided directional atherectomy is technically feasible and may aid in achieving maximal plaque debulking and reduce the amount of subintimal injury.

Abstract

Although coronary atherosclerosis most commonly produces clinical effects as a result of stenosis, aneurysmal disease also occurs. We have found an increased prevalence of ectasia and aneurysmal disease in familial hypercholesterolemia (FH) suggesting a link between plasma lipoproteins and coronary aneurysms.In 197 asymptomatic subjects with FH, we examined the prevalence of ectasia and its association with coronary risk factors. An ectatic segment was defined as one with a luminal diameter > 1.5 times that of the adjacent normal segment, excluding poststenotic dilation. Among subjects with FH, 15% had ectasia compared with 2.5% of an age- and sex-matched control group of 198 subjects without FH presenting for coronary angiography (P < .001). These control patients had significantly more severe coronary atherosclerosis than patients with FH. Ectasia was 3 times more common in men than women (P < .025). Neither age nor hypertension was predictive. Although in part reflecting the striking sex differential, ectasia was strongly associated with a lower HDL cholesterol level (P = .003), a higher LDL/HDL ratio (P = .003), and to a lesser extent, a higher LDL cholesterol level (P = .07). No association was found with plasma triglycerides or very low-density lipoprotein cholesterol levels. Among FH patients, ectasia was strongly associated with an overall index of occlusive atherosclerotic disease, based on quantitative angiography (P = .004). Intracoronary ultrasound interrogation of aneurysmal segments revealed circumferential intimal thickening.Coronary ectasia is more prevalent in patients with FH than in other patients with coronary atherosclerosis and shows a strong inverse association with HDL cholesterol levels. This suggests that disordered lipoprotein metabolism in FH may predispose patients to aneurysmal coronary artery disease.

Abstract

Current knowledge of lumen and plaque shape of atherosclerotic coronary vessels is derived from in vitro examination of coronary vessels. The in vivo plaque and lumen shape was studied by intracoronary ultrasound (ICUS) imaging in 82 patients with coronary artery disease and the images were analyzed by computerized morphometry. In 386 of the 638 cross sections (61%) with atherosclerotic plaque, nondiseased wall (intima thickness < 200 microns) was present in the ICUS image; in 440 sections (69%), the plaque was located eccentrically in the vessel. Although the extent of nondiseased wall segment and eccentricity decreased with plaque burden, 42% of cross sections with plaque stenosis > 60% had residual nondiseased wall, and 40% of these cross sections showed eccentric plaque. A circular or near-circular lumen (ratio of long/short diameter < 1.1) was found in 252 cross sections (39%), an elliptical lumen in 370 (58%), and a "D"-shaped lumen in 16 cross sections (3%); slit- or star-like lumen shapes were not detected. The ratio of long/short diameter was lower in the 555 noncalcified (1.10 +/- 0.08) than in the 83 calcified cross sections (1.15 +/- 0.08; p < 0.001). Radiographic lumen area measurements were simulated in ellipse models based on the long and short lumen axes measured in the ICUS images. Assuming a single radiographic view, maximal over- or underestimation of up to 40% compared with the true vessel lumen is possible. Errors in lumen area measurements increased with plaque area stenosis, reflecting the more elliptical lumen shape in advanced coronary disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract

The purpose of this study was to describe our preliminary experience using catheter-based intracardiac echocardiography as an adjunct to biplane fluoroscopy for guiding radiofrequency catheter ablation of atrial arrhythmias in the right side of the heart.Catheter ablation requires precise positioning and stable ablation electrode-endocardial contact. This procedure is currently guided by an analysis of intracardiac electrograms and fluoroscopy. However, the use of fluoroscopy does not allow the endocardium and certain anatomic landmarks to be identified and is associated with the hazards of radiation exposure.Seventeen symptomatic patients were studied. A 10F 10-MHz intracardiac imaging catheter was used to visualize specific anatomic landmarks in the right atrium for directing the ablation electrode in 15 patients undergoing radiofrequency ablation of 19 arrhythmias and to assist with interatrial septal puncture in 3 patients.Continuous intracardiac imaging was performed for a mean +/- SD of 63.6 +/- 39.2 min and demonstrated distal electrode-endocardial tissue contact in 81 (60%) of 134 radiofrequency applications. Movement of the catheter was demonstrated during 36 (44%), microcavitations during 39 (48%) and thrombus during 15 (19%) of the 81 imaged applications. In 7 of 10 procedures for atrial flutter, successful ablation was directed at anatomic corridors in the right atrium visualized with intracardiac echocardiography. During ablation of atrial tachycardia, imaging identified abnormal atrial anatomy related to previous surgery and guided successful ablation of a reentrant tachycardia circulating around these anatomic obstacles. In two procedures for slow pathway modification of atrioventricular node reentrant tachycardia, intracardiac echocardiography confirmed catheter stability at the tricuspid annulus anterior to the coronary sinus.During catheter ablation, intracardiac echocardiography augments fluoroscopy by visualizing anatomic landmarks, ensuring stable endocardial contact and assisting in transseptal puncture. Ablation of typical atrial flutter can be successfully directed at anatomic corridors identified using intracardiac imaging.

Abstract

Measurements of lumen and plaque dimensions by intracoronary ultrasound imaging are useful in assessing effects of intracoronary interventions and in quantifying plaque burden in transplant patients or during regression trials. However, these measurements are affected by inter- and intraobserver variability. In 87 patients, 120 intracoronary ultrasound images were obtained with a 4.3F, 30 MHz catheter. Morphometric measurements were performed two times by three independent observers using computerized planimetry. Intraobserver and interobserver agreement for qualitative parameters (presence of atherosclerotic plaque, calcified plaque, and residual nondiseased wall) was high (> 87%). For quantitative parameters measured directly in the images (lumen area, minimal and maximal lumen diameters, area within the internal elastic lamina, arc of calcium plaque) interobserver and intraobserver correlation between measurements was high (correlation coefficient r > 0.90) and differences between measurements were low (mean differences < 10%; SD < 20%). Measurement of the arc of nondiseased wall showed less interobserver correlation (r = 0.76 to 0.91), but percentages of difference between the measurements were low. Parameters derived from directly measured variables (plaque area, area stenosis, thickness, and eccentricity) showed slightly higher variability (correlations between measurements r = 0.78 to 0.91). SD for percentages of difference ranged between 20% and 30% (plaque area, area stenosis, and thickness) and systematic deviation between measurements (mean differences > 10%) occurred for plaque area. Thus most qualitative and quantitative measurements of lumen and plaque dimensions performed in intracoronary ultrasound images have low in intraobserver and interobserver variability; derived parameters may have slightly higher variability. Variability of morphometric measurements has to be considered, especially when serial ultrasound measurements are compared.

Abstract

This study was designed to examine the accuracy of intravascular ultrasound in detecting different histologic types of calcium pattern in human coronary artery atherosclerotic lesions. Previous studies have shown that calcium deposits in atherosclerotic lesions may occur in various forms and that intravascular ultrasound is a sensitive technique to detect calcium in atherosclerotic lesions. However, there has been no distinction between varying image representations of calcium and different histologic patterns of intralesional calcific deposits. Calcific lesions have an important clinical impact on the outcome of intracoronary transcatheter therapy, and the varying types of calcium may also play a role in the guidance of intracoronary interventions. Fifty fresh coronary vessel segments were studied by intracoronary ultrasound imaging and the images compared with the corresponding histologic sections. With intracoronary ultrasound imaging, calcium was defined as bright echo with corresponding sharp edged shadowing in the distal field. Three different histologic types of calcification were defined, and the sensitivity and specificity of the detection by intravascular ultrasound were determined for each type. Dense calcified plaques (type 1) were found 18 cases, microcalcification (small flecks of calcium) with single calcium fleck size < or = 0.05 mm (type 2) in 12 cases, and combination of calcified plaque surrounded by small calcium flecks (type 3) in 3 cases. In 17 (34%) coronary vessel segments, histologic analyses detected no calcium. Intracoronary ultrasound correctly detected 16 (89%) of 18 cases of type 1 calcification, 2 (17%) of 12 type 2, and all 3 (100%) type 3. Sensitivity for detection of type 1 and 3 calcification was 90%, with specificity of 100%.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract

Abnormal shear rates of blood flow have been implicated in the processes of thrombosis, atherosclerosis, and restenosis after angioplasty. However, no study has quantitated the effect of stenosis inlet geometry on the shear rates in the region upstream to the stenosis. To quantitate this effect, we measured the velocity profiles of blood flow at Reynolds numbers 175 and 350 upstream to different axisymmetric model stenoses in an excised canine aorta. Two 40% and two 75% stenoses were tested, one each with a 45-degree inlet angulation and one each with a 90-degree angulation. For the velocity measurements we used a specially developed external single-channel Doppler ultrasound system capable of resolving blood flow velocity at 91 microns radial intervals across the aorta. We found that increasing the severity of stenosis narrowing and angulation resulted in a significant decrease in shear rate at the endothelial surface (40%/45-degree stenosis: 189 +/- 46 sec-1 vs 75%/90-degree stenosis: 49 +/- 12 sec-1 at Reynolds number 350; p < 0.002) and a significant increase in the maximum shear rate within the vessel lumen (189 +/- 46 sec-1 vs 295 +/- 8 sec-1, respectively; p < 0.05) in the region immediately upstream to the stenosis. These effects were less pronounced for Reynolds number 175. We conclude that stenosis inlet geometry has a significant impact on the flow conditions in the region immediately upstream to the stenosis, which is dependent on the Reynolds number. This may be an important determinant of thrombosis and atherogenesis in this particular region.

Abstract

This study evaluates two key parameters influencing the ultrasonic backscatter from blood--hematocrit and flow rate--at 30 MHz in an in vitro flow system. A range of hematocrits from 0 to 50% was studied at a constant flow rate; various flow rates between stagnation and physiologic levels were studied at a constant hematocrit. The relation between backscatter intensity and hematocrit was a convex function with a maximum between a hematocrit of 10% and 20%. In the flow rate studies, the blood backscatter intensity was a maximum at a flow rate of 0 and rapidly decreased at higher flow rates. These in vitro results suggest that blood backscatter intensity is minimally dependent on hematocrit in the physiologic range. However, a dramatic increase in backscatter intensity occurs with stagnant flow, presumably the result of red blood cell aggregation. Clinically, blood backscatter intensity may provide an index for risk of thrombus formation.

Abstract

Abnormal arterial blood flow patterns have been implicated as etiologic factors in thrombosis and atherosclerosis. Intravascular pulsed Doppler ultrasound techniques with fast-Fourier transform analysis offer the opportunity to measure these abnormalities. The authors hypothesized that statistical analysis of radial-directed beam spectra could be used to distinguish disturbed from non-disturbed flow and that analysis of conventional axial-directed beam spectra could then be used to distinguish laminar high-shear from laminar low-shear flow. They developed a scaled-up in-vitro model of coronary flow consisting of a glycerol/H2O test fluid flowing through an acrylic cylinder at Reynolds numbers spanning the typical physiologic range within the coronary arteries. A scaled-up Doppler catheter with the capacity for 90 degrees reflection of the beam was placed centrally. Disturbed flow was created by introducing a flow screen, and altered shear rates were produced by changing the Reynolds number. For the radial-directed beam studies, the coefficients of variation of the Doppler spectra for the disturbed flow states were significantly greater than for the nondisturbed flow states (p less than 0.01). For the axial-directed beam studies, the coefficients of variation of the Doppler spectra for the laminar high-shear flow states were significantly greater than for the laminar low-shear flow states (p less than 0.01). They conclude that abnormal blood flow patterns can be differentiated by the selective use of radial-directed and axial-directed Doppler catheter recordings.

Abstract

The coronary Doppler catheter has been used primarily in the measurement of coronary vasodilator reserve, most often as the ratio of peak to resting velocity in response to an intracoronary dose of papaverine. We have developed a new method based on the continuity equation using a Doppler catheter for the assessment of stenosis severity in the coronary circulation by means of quantitative velocity measurements obtained by complex spectral analysis of the Doppler signal. With this system we have been able to detect a high-velocity stenosis jet in a canine model of coronary stenosis of known cross-sectional area. Using the peak velocity obtained by complex spectral analysis, we found a strong correlation between cross-sectional areas determined by the continuity equation and known cross-sectional areas (r = 0.93, SEE = 0.23 mm2). We also found a strong correlation between the ratio of peak stenosis velocity to proximal vessel velocity and percent diameter and percent area stenosis (r = 0.91 and 0.92, respectively). When the velocity was determined with conventional zero-crossing methods for these parameters, there was no correlation between calculated and known values for cross-sectional area and percent diameter or area stenosis. Measurements of the vasodilator reserve in response to intracoronary papaverine before and after implantation of the stenosis did not correlate with any of the anatomic parameters of stenosis severity regardless of the method of signal analysis (zero-crossing or complex spectral analysis). The measurement of quantitative peak coronary velocity with a Doppler catheter using complex spectral analysis may provide an accurate method for determining the severity of a coronary stenosis.

Abstract

We studied 16 patients with chronic aortic insufficiency to compare a method for measuring regurgitant volume with color Doppler flow mapping to stroke count ratio determined by radionuclide ventriculography and to ventricular volumes assessed by two-dimensional echocardiography. A real-time color flow map of the left ventricular was obtained from an apical two- and five-chamber view and the maximal mosaic pattern of diastolic turbulent flow was planimetered as a reflection of the maximal regurgitant volume using biplane Simpson's rule. The maximal Doppler regurgitant volume evaluated by color Doppler flow mapping correlated with the stroke count ratio measured by scintigraphy (r = 0.86, SEE = 11 cc). There were significant relationships between maximal regurgitant volume measured by color Doppler and echocardiographic left ventricular end-diastolic volume (r = 0.88), left ventricular end-systolic volume (r = 0.77), and left ventricular mass (r = 0.71). Patients with larger regurgitant volumes tended to have a larger left ventricular end-diastolic volume-to-mass ratio (r = 0.56). Thus maximal aortic regurgitant volume can be estimated noninvasively with color Doppler flow mapping. The measurement appears to relate to left ventricular morphologic changes occurring in this condition and it may prove to be useful in assessing patients with chronic aortic insufficiency and in determining their long-term management.

Abstract

The continuous wave Doppler ultrasound signal across the left ventricular outflow tract in hypertrophic cardiomyopathy has a characteristic pattern that is in keeping with the dynamic nature of the pressure gradient in this condition. To determine the accuracy and reliability of the peak Doppler flow velocity signal for measuring the peak pressure gradient in this condition, 340 beats were analyzed from five consecutive patients studied with simultaneous continuous wave Doppler ultrasound and dual catheter pressure recordings across the left ventricular outflow tract. Each patient was studied at steady state and during physiologic and pharmacologic manipulations of the pressure gradient. Peak velocity and calculated peak gradient were determined by two independent observers who did not know the catheter measurements. In addition, 18 beats with well defined flow velocity envelopes were digitized for analysis of the magnitude, timing and contour of the instantaneous Doppler ultrasound and catheter gradients throughout systole. Peak catheter gradient in the 340 beats ranged from 12 to 245 mm Hg. The correlations between the Doppler-derived and catheter peak gradients were close (r = 0.96, SEE = 4 mm Hg for Observer 1 and r = 0.97, SEE = 11 mm Hg for Observer 2). Interobserver variability for measurement of peak flow velocity was small (mean +/- SD 0.16 +/- 0.15 m/s). An interobserver difference greater than 0.3 m/s occurred in 25 of the 340 beats analyzed. By retrospective analysis, this was due to contamination of the outflow tract signal by mitral regurgitation.(ABSTRACT TRUNCATED AT 250 WORDS)

DOPPLER ECHOCARDIOGRAPHIC MEASUREMENT OF AORTIC-VALVE AREA IN AORTIC-STENOSIS - A NONINVASIVE APPLICATION OF THE GORLIN FORMULAJOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGYTeirstein, P., Yeager, M., Yock, P. G., Popp, R. L.1986; 8 (5): 1059-1065

Abstract

Thirty adult patients with aortic stenosis had Doppler echocardiography within 1 day of cardiac catheterization. Noninvasive measurement of the mean transaortic pressure gradient was calculated by applying the simplified Bernoulli equation to the continuous wave Doppler transaortic velocity recording. Stroke volume was measured noninvasively by multiplying the systolic velocity integral of flow in the left ventricular outflow tract (obtained by pulsed Doppler ultrasonography) by the cross-sectional area of the left ventricular outflow tract (measured by two-dimensional echocardiography). Non-invasive measurement of aortic valve area was calculated by two methods. In method 1, the Gorlin equation was applied using Doppler-derived mean pressure gradient, cardiac output and systolic ejection period. Method 2 used the continuity equation. These noninvasive measurements were compared with invasive measurements using linear regression analysis, and mean pressure gradients correlated well (r = 0.92). Aortic valve area by either noninvasive method also correlated well with cardiac catheterization values (method 1, r = 0.87; method 2, r = 0.88). The sensitivity of Doppler detection of critical aortic stenosis was 0.86, with a specificity of 0.88 and a positive predictive value of 0.86. Cardiac output measured nonsimultaneously showed poor correlation (r = 0.51). Doppler echocardiography can distinguish critical from noncritical aortic stenosis with a high degree of accuracy. Measurement of aortic valve area aids interpretation of Doppler-derived mean pressure gradient data when the gradients are in an intermediate range (30 to 50 mm Hg).

PATTERNS AND TIMING OF DOPPLER-DETECTED INTRACAVITARY AND AORTIC FLOW IN HYPERTROPHIC CARDIOMYOPATHYJOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGYYock, P. G., Hatle, L., Popp, R. L.1986; 8 (5): 1047-1058

Abstract

This study describes the velocity characteristics of left ventricular and aortic outflow in 25 patients with hypertrophic "obstructive" cardiomyopathy. Systematic pulsed and continuous wave Doppler analysis combined with phonocardiography and M-mode echocardiography was used to establish the pattern and timing of outflow in the basal and provoked states. This analysis suggests that 1) the high velocity left ventricular outflow jet can be reliably discriminated from both aortic flow and the jet of mitral regurgitation using Doppler ultrasound; 2) the Doppler velocity contour responds in a characteristic fashion to provocative influences including extrasystole and Valsalva maneuver; 3) the onset of mitral regurgitation occurs well before detectable systolic anterior motion of the mitral valve; 4) left ventricular flow velocities are elevated at the onset of systolic anterior motion of the mitral valve, suggesting a significant contribution of the Venturi effect in displacing the leaflets and chordae; 5) the high velocities of the outflow jets are largely dissipated by the time flow reaches the aortic valve; and 6) late systolic flow in the ascending aorta is nonuniform, with formation of distinct eddies that may contribute to "preclosure" of the aortic valve.

Abstract

The accuracy of Doppler-estimated pressure gradients in the setting of irregular, multiple, and tunnellike stenoses was investigated. An in vitro model of the left ventricular outflow tract was designed to allow pulsatile flow of red cells in saline across valve orifices from 0.01 to 2.5 cm2. Simultaneous pressure gradients were estimated by both Doppler and direct-pressure manometer techniques. Gradients obtained by the two methods correlated well for valve areas in the range of clinical stenoses at pressure gradients of 10 to 150 mm Hg (r = .97 to .99). Model valves were constructed with a large orifice (0.75 to 1.25 cm2) placed beside a small orifice (0.02 to 0.25 cm2) in the same outflow tract. A distinct jet was recorded when the Doppler transducer was aligned with each orifice. Doppler-estimated gradients for each pair of large and small orifices were identical and correlated well with those measured by manometer (r = .97 to .99). Irregularly shaped orifices also provided good correlation between the two methods (r = .98 to .99). Pulsatile flow was generated through long tunnellike obstructions with cross-sectional areas varying from 0.06 to 1.25 cm2. Tunnel length varied from 0.1 to 4 cm. Tunnel areas above 0.25 cm2 gave good Doppler-to-manometer correspondence at all tunnel lengths. Doppler underestimated manometer-determined values in the 0.25 cm2 tunnel by 8% at 3 cm and by 15% at 4 cm. In the 0.06 cm2 tunnel, Doppler underestimated manometer gradients by 12%, 15%, 32%, and 42% at lengths of 1, 2, 3, and 4 cm, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)